The amine as carbonyl precursor in the chemoenzymatic synthesis of Passerini adducts in aqueous medium

Article abstract of DOI:10.1016/j.catcom.2020.106118

A new simple environmentally friendly protocol based on sequential chemoenzymatic synthesis of α-acyloxy carboxyamides from amines as a carbonyl precursor is presented. For the synthesis of the desired products, biocatalytic process combining laccase/TEMPO oxidation of amine followed by Passerini reaction was developed. After a careful optimization of the reaction conditions only one of desired Passerini reaction products was obtained despite of the presence of two different carboxylic acids in reaction medium. The developed protocol offers a chemoselective and environmentally friendly procedure for the synthesis of various α-acyloxy amides with good to excellent yields.

Full text of DOI:10.1016/j.catcom.2020.106118

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The amine as carbonyl precursor in the chemoenzymatic synthesis
of Passerini adducts in aqueous medium
Arleta Madej, Dominik Koszelewski, Daniel Paprocki, Anna
Brodzka, Ryszard Ostaszewski
PII:
S1566-7367(20)30194-1
DOI:
https://doi.org/10.1016/j.catcom.2020.106118
CATCOM 106118
Reference:
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
16 April 2020
14 July 2020
15 July 2020
Please cite this article as: A. Madej, D. Koszelewski, D. Paprocki, et al., The amine
as carbonyl precursor in the chemoenzymatic synthesis of Passerini adducts in aqueous
medium,
Catalysis
Communications
(2019),
https://doi.org/10.1016/
j.catcom.2020.106118
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The amine as carbonyl precursor in the chemoenzymatic synthesis
of Passerini adducts in aqueous medium
Arleta Madej, Dominik Koszelewski, Daniel Paprocki, Anna Brodzka and Ryszard Ostaszewski*
Institute of Organic Chemistry Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
Corresponding author: E-mail:ryszard.ostaszewski@icho.edu.pl
Abstract
A new simple environmentally friendly protocol based on sequential chemoenzymatic
synthesis of α-acyloxy carboxyamides from amines as a carbonyl precursor is presented. For
the synthesis of the desired products, biocatalytic process combining laccase/TEMPO
oxidation of amine followed by Passerini reaction was developed. After a careful optimization
of the reaction conditions only one of desired Passerini reaction products was obtained
despite of the presence of two different carboxylic acids in reaction medium. The developed
protocol offers a chemoselective and environmentally friendly procedure for the synthesis of
various α-acyloxy amides with good to excellent yields.
Keywords: chemoenzymatic, Passerini, laccase, enzyme, oxidation, amine
1
. Introduction
The amines are important nitrogen-containing building blocks for the synthesis of valuable
compounds applied in medicinal chemistry,[1] drug discovery programs,[2] combinational
chemistry,[3] natural product synthesis,[4] agrochemistry[5] and polymer chemistry[6]. Moreover,
naturally occurring amines such as adrenaline, histamine, serotonine, thiamine chloride, tyramine
are essential for living organisms.[7] Therefore, chemists inspired by natural metabolic processes of
amines try to develop new catalytic processes engaging amines as the substrates. Thus, the
biomimetic oxidation reaction seems to be very attractive approach which resembles biological
processes. Among all metabolites of biogenic amines, α-keto acids, aldehydes or other oxidized
forms of amine-containing products are of particular significance.[8] The natural degradation of
amines via their transformation into aldehydes is important process for organic chemistry.
Currently, the selective generation of aldehydes is fundamental reaction [9] as they are important
synthons and intermediates.[10] They are high-value components for the perfume or food industry
as well.[11] Common procedures for the synthesis of aldehydes are based on the oxidation of
alcohols or reduction of carboxylic acids.[12] However, many oxidation systems require harsh
reaction conditions and produce metal-containing wastes which are intolerable for pharmaceutical
or cosmetic industry.[13] Therefore, the development of new methods of generation of aldehydes in
situ using metal-free methodologies is still desired. Interesting alternatives for the synthesis of
aldehydes under mild and sustainable conditions are biocatalytic processes.[14] For example,
primary amines can be oxidized to aldehydes by copper amine oxidases (CAOs) through redox
cofactor and molecular oxygen. [15] Yoshida et al. reported enzymatic oxidation of vanillylamine by
amine oxidase from Aspergillus niger as the one of the method for the synthesis of vanillin (4-
hydroxy-3-methoxy benzaldehyde), an important flavor component of vanilla.[16-17] The amine
dehydrogenases (AmDH) were applied for the oxidation of amines to carbonyl compounds in
the presence of cofactors e.g. tryptophan tryptophyquinone (TTQ) or NAD(P).[18-19] However,
these methods are limited by high cost of enzymes and cofactors.
In recent years, the selective enzymatic oxidation of wide range of electron-rich compounds in
aqueous medium has been extensively studied. In this context the group of multi-copper oxidases
such as laccase (EC 1.10.3.2) plays the important role.[20] Giacomini’s group reported the selective
oxidation of amines to aldehydes or imines via laccase using TEMPO as mediator and oxygen as an

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electron acceptor.[21] Due to a great interest of metabolic processes, the application of aqueous
liposomes solution in organic synthesis is of great importance. The usage of liposomes allows
to replace an organic solvent by an aqueous surfactant system resembling the protocells
model.[22-23] Interesting example of the use of liposomes as a protocells model is the synthesis of
peptidomimetics.[24] The convenient method of peptidomimetics synthesis is based on Passerini
reaction, an advanced tool used in medicinal chemistry and drug discovery.[25] According to the
literature data, Passerini reaction can be successfully performed in the presence of liposomes.[26]
However, due to the instability of aldehydes, the development of alternative sequential process
combining an oxidation reaction with Passerini reaction is highly important.[27] There are several
literature-known protocols for the one-pot oxidation followed by Passerini reaction. In recent years,
our group has presented the important role of laccase from Trametes versicolor (TvL) in
chemoenzymatic sequential oxidation of benzyl alcohol followed by Passerini reaction.[28]
However, these methods are limited for oxidation of alcohols. The only example of the oxidative
coupling of primary amines and its application for Ugi reaction involves the usage of harsh oxidant
such as IBX.[29] To the best of our knowledge, oxidation of amines has yet not been attempted to
obtain products of Passerini reaction under environmentally friendly conditions. Herein, we report
the first synthesis of α-acyloxy carboxyamides using amines as a carbonyl precursor (Scheme 1).
For this purpose the chemoenzymatic sequential reaction based on bioremediation of benzyl
amines via TvL/TEMPO system followed by Passerini reaction was studied. The studied reaction
was carried out in the aqueous medium under air atmosphere.
Scheme 1. The synthesis of α-acyloxy carboxyamides from amines as a carbonyl precursor.
2
. Results and Discussion
Initial studies were focused on bioremediation of benzyl amine into benzaldehyde under
Passerini reaction conditions in the vesicular medium. According to the literature data,
the benzyl amine (1a) can be oxidized by laccase from Trametes versicolor (TvL) to the
corresponding aldehyde (2a) in the acetic buffer pH 5.2 [21]. Moreover, Giacomini’s group
showed the significant influence of acetic acid on the oxidative deamination of amine in
distilled water. [21] To the best of our knowledge, the acetic buffer is not an efficient solvent
for Passerini reaction. As we previously reported, the phosphate buffer pH 5.2 is optimal for
TvL/TEMPO oxidation of benzyl alcohol and followed Passerini reaction. [28] Therefore, the
optimal conditions of oxidative deamination of benzyl amine such as the amount of TEMPO,
laccase from Trametes versicolor and acetic acid in phosphate buffer were studied (see
Supporting Information). The full conversion of amine 1a into aldehyde 2a was detected on
GC when the reaction was conducted in phosphate buffer with addition of 1 eq of acetic acid.
Table 1. The influence of carboxylic acids on the oxidative deamination of benzyl amine.

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Carboxylic acid
Yield of 2a (%)a,b
1.
2.
3.
4.
5.
6.
7.
8.
9.
-
56
99
99
67
62
72
53
65
84
Acetic
Propionic
Benzoic
Phenylacetic
Oleic
Stearic
Caprylic
Lauric
[
a] Reaction conditions: benzylamine (1a, 0.25 mmol); carboxylic acid (0.25 mmol); TEMPO (0.05
mmol); laccase from Trametes versicolor (25U) in 2.5 mL of phosphate buffer (100 mM, 5.2 pH) were
mixed for 24 h at 30°C. [b] The reaction yield was determined on GC area
In the next set of experiments, we investigated the influence of various carboxylic acids on
oxidative deamination of amine in aqueous medium (Table 1). The enzymatic oxidation
performed in water without the addition of any carboxylic acids resulted in the formation of
aldehyde in 56% of yield. The best results were obtained in the presence of acetic and
propionic acids giving product 2a quantitatively (Table 1, entries 2 and 3, respectively). The
addition of aromatic acids such as benzyl or phenylacetic acids led to the formation of the
product 2a with 62-67% of yield (Table 1, entries 4 and 5). Moreover, we were also interested
if carboxylic acids can promote oxidation of amine as well as the multicomponent reaction.
According to our previous research [30], the application of micelle- or vesicle-forming fatty
acids as substrates for Passerini reaction promote this reaction in water only (without the
addition of surfactant). For this purpose different fatty acids (such as caprylic, lauric, stearic,
oleic acids) which are also known to form micelles and/or vesicles were tested (Table 1,
entries 6-9). The reaction carried out with lipophilic, high-melting stearic acid provided
product 2a with lower yield than in water (56% vs 53%; Table 1, entries 1 and 7). The
application of caprylic, oleic or lauric acids slightly improved the reaction course (Table 1,
entries 6-9). As the best result was obtained in the presence of acetic acid, this compound was
selected for further studies.
In the next step, the influence of surfactants on the oxidation process was studied. We tested
series of surfactants including non-ionic, cationic, anionic and zwiterrionic surfactants.
However, for all performed experiments, the addition of surfactant gave aldehyde 2a with
lower yield than in water only (see Supporting information). When cationic surfactants such
as DDAB (didodecyldimethylammonium bromide) or DODAB(dimethyldioctadecylammonium
bromide) were used, the desired aldehyde was obtained with 80 and 87% yield, respectively.
With this data in hand, the one-pot chemoenzymatic sequential oxidation-Passerini reaction
was performed. For the model reaction benzyl amine (1a), benzoic acid (3a) and benzyl
isocyanide (4a) were selected as substrates. For the first 24 hours, an enzymatic oxidative
deamination of 1a with acetic acid and lacccase/TEMPO system took place and then benzoic
acid and benzyl isocyanide were added. The proposed protocol may lead to the formation of
two products of Passerini reaction: 2-(benzylamino)-2-oxo-1-phenylethyl benzoate (5a) and
2-(benzylamino)-2-oxo-1-phenylethyl acetate (5b). First, the studies on the combination of
the oxidative deamination of benzyl amine with subsequent Passerini reaction in aqueous
solvents were performed (Table 2).

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Table 2. The studies on chemoenzymatic sequential oxidation-Passerini reaction
Solvent
Water
Water
Surfactant
-
Yield of 5a (%)a,d
Yield of 5b (%)a
1.
2.
3.
4.
5.
6.
40
64
59
45
72
51
-
-
-
-
-
-
b
DODAB
DODAB
c
Water
PBS 5.2pH
PBS 5.2 pH
PBS 5.2 pH
-
b
DODAB
DODAB
c
[a] Reaction conditions: benzylamine (1a, 0.25 mmol); acetic acid (0.25 mmol); TEMPO (0.05 mmol);
laccase from Trametes versicolor (25U) were mixed in 2.5 mL of solvent for 24 h at 30°C. Then, benzoic
acid (3a, 0.25 mmol) and benzyl isocyanide (4a, 0.25 mmol) were added and the reaction was stirred
for additional 24 h. [b] DODAB (20 mol%) was added after oxidation step. [c] The oxidation was carried
out in the presence of DODAB (20 mol%).[d] The yield of isolated product.
During our studies, we performed proposed reactions in distilled water or in phosphate
buffer (5.2 pH), a common solvent used for oxidation reaction via laccase from Trametes
versicolor.[28] Moreover, we were interested whether the chemoenzymatic sequential
oxidative deamination of amine 1 to aldehyde 2 followed by Passerini reaction can be
achieved in the presence of liposomes. Therefore, the chemoenzymatic sequential one-pot
oxidation-Passerini reaction in distilled water in the presence of 1 eq of acetic acid were
performed. Among all expected products, compound 5a was obtained as the only product
with 40% yield (Table 2, entry 1). Although the oxidation of amine in the presence of acetic
acid in water proceeded quantitative, the yield of 5a was not satisfying for the whole process.
Based on our previous work, the reaction efficiency could be improved by the addition of
protocells (aggregates of surfactants). [26,28] Thus, in the next step we have studied the
impact of DODAB on chemoenzymatic sequential reaction efficiency. Two various cases were
tested - when both reaction steps were carried out in the presence of DODAB (Table 2, entry
3
) or when the surfactant was added after the oxidation step (Table 2, entry 2).
In both cases the product of 5a was obtained with good yield, however the slightly better
results was observed when DODAB was applied only for second reaction step (Table 2, entry
2
). Moreover, we have also performed similar experiments used phosphate buffer pH 5.2 as
medium (Table 2, entries 4-6). Comparing the chemoenzymatic sequential reaction
performed in distilled water with reaction in PBS (5.2 pH), product 5a was obtained with
better yield when PBS was used as reaction medium (Table 2, entry 5). As the stability and
activity of laccase from Trametes versicolor strictly depend on reaction conditions such as e.g.
pH, concentration of surfactant, temperature, [31-34] we have also performed the studies on
the optimization of reaction conditions such as time, type and concentration of surfactant, pH
value (Supporting Information). The obtained results showed that the best efficiency was

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observed when the chemoenzymatic sequential reaction was conducted in PBS pH 5.2 in the
presence of 20 mol% of DODAB during 48 hours, providing product of 5a with 72% yield.
With the optimized reaction conditions in hand, the generality and scope of this new
procedure were performed providing to α-acyloxycarboxamides 5a-5s (Scheme 2). The series
of experiments with various aromatic amines 1, carboxylic acids 3 and isocyanides 4 were
carried out in the presence of surfactants. The amine 1 was mixed with laccase, TEMPO and
acetic acid in phosphate buffer at 30 °C. Then, after 24hours DODAB as well as 3 and 4 were
added and resulted mixture was stirred for 24 hours at 30°C. When benzyl amine 1a, various
acids 3 and benzyl isocyanide 4a were used as substrates, Passerini reaction products 5a-5i
were isolated with yields up to 72%. The application of acetic acid and propionic acid as
substrates resulted in the formation of products 5b and 5c with 16% and 23% yield,
respectively. The reaction with phenylacetic acid gave product 5d with 66% yield. Then, the
application of sustainable acids was verified. The chemoenzymatic sequential reactions with
caprylic, lauric, stearic, oleic acids gave products 5e-5h up to 48%. The best results were
obtained when the caprylic (46%) or lauric acids (48%) were used. Additionally, the influence
of DODAB protocells on the diastereoselectivity of Passerini reaction was studied. For this
purpose, the reaction with benzyl amine 1a, (S)-naproxen 3i and benzyl isocyanide 4a was
performed. The product 5i was obtained with 40% yield as a mixture of diastereomers (dr:
1
:1). Next, the influence of different isocyanides on chemoenzymatic sequential reaction
course was investigated. The model reraction with p-methoxybenzyl isocyanide gave product
j with 60% yield. The reaction with n-butyl 4l and cyclohexyl isocyanide 4k resulted in the
5
formation of products 5k and 5l (51% and 66% of yield, respectively). The change of benzyl
amine 2a  resulted in the formation of product 5m with 71%
yield. The Passerini reaction with phenylacetic acid gave products 5n and 5o (71% and 21%,
respectively). Reaction with p-methoxybenzyl isocyanide and cyclohexyl isocyanide resulted
in product 5p and 5r with yield about 72%. The use of 1,1,3,3-tetramethylbutyl isocyanide
gave low yield of 5s (23%). In any of cases, the formation of the Passerini reaction products
form acetic acids were not observed. This indicates that proposed methodology is
chemoselective in the presence of protocells model.

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Reaction conditions: benzylamine (1a, 0.25 mmol); acetic acid (0.25 mmol); TEMPO (0.05 mmol),
laccase from Trametes versicolor (25U) were mixed in 2.5 mL of phosphate buffer (100 mM, pH 5.2) for
2
4 h at 30°C. Then, DODAB (20 mol%), carboxylic acid (3, 0.25 mmol) and isocyanide (4, 0.25 mmol)
were added. Then, the reaction was stirred for additional 24h. Isolated yield. [a] Mixture of
diastereoisomers, dr = 1 : 1
Scheme 2. Scope and limitation of the TvL/TEMPO oxidation P-3CR system.
Next, we were interested whether carboxylic acid can promote oxidation of amine as well as
be used as a substrate in subsequent Passerini reaction. On this purpose four carboxylic acids
such as acetic acid, propionic acid, benzoic acid and phenylacetic acid were selected. They
were initially used to promote oxidative deamination of 1a to 2a. Additionally, the
experiments in which second equivalent of the same carboxylic acid is added after oxidation
step were performed. However, among all selected acid only the reaction with acetic acid gave
satisfying results (see Supporting Information). As the addition of lauric acid promotes
successfully the oxidation of benzylamine (Table 1, entry 9), we have also tested if this acid
can be used as a surfactant in Passerini reaction (instead of DODAB)[29] thus all steps of
proposed reaction could be conducted in the presence of lauric acid (Scheme 3).

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Scheme 3. Chemoenzymatic sequential Passerini reaction in the presence of lauric acid.
To gain this goal, the chemoenzymatic sequential reaction in the presence of lauric acid was
performed (Scheme 3). The reaction with benzyl amine (1a), laccase/TEMPO system and
lauric acid was carried out for the first 24hrs and then benzoic acid (3a) and benzyl
isocyanide (4a) were added. The addition of lauric acid has beneficial influence on all steps of
sequential reaction leading to the formation of product 5a with 50% yield. The by-product of
Passerini reaction with lauric acid was observed only on TLC and was not isolated.
3. Conclusions
We have developed a new environmentally friendly chemoselective one-pot chemoenzymatic
oxidation-Passerini reaction in the presence of protocells model. For the first time the amines
were used as precursors of carbonyl compounds to the synthesis of α-acyloxy carboxyamides.
The methodology based on the TvL/TEMPO oxidation of amines followed by Passerini
reaction in the presence of protocells of DODAB was established. To improve efficiency of
oxidative deamination of amines, the addition of acetic acid was needed. To make the
procedure more sustainable, fatty acids were also used as substrates for Passerini reaction or
to promote the oxidative deamination of amine. After detailed optimization of reaction
conditions, the scope of substrates was investigated. In all cases only one product of Passerini
reaction was received with good to excellent yield what indicates the chemoselective course
of Passerini reaction in the aqueous medium. Aditionally the developed methodology is free
from transition metal, harsh oxidants or organic solvents what is desirable from an
environmental point of view.
4
. Expermental section
Experimental details and characterization of products are given in Supporting Information.
Acknowledgements
This work was supported by the National Science Center, Poland project Opus No.
2
016/23/B/ST5/03307.
References
1] S. Kłossowski, A. Muchowicz, M. Firczuk, M. Świech, A. Redzej, J. Golab, R. Ostaszewski,
[
Studies toward Novel Peptidomimetic Inhibitors of Thioredoxin–Thioredoxin Reductase
System, J. Med. Chem. 55 (2012) 55-67. https://doi.org/10.1021/jm201359d.
[
2]
E. Ruijter, R. V. A. Orru, Multicomponent reactions – opportunities for the
pharmaceutical industry. Drug Discovery Today Technol. 10 (2013) e15-20.
https://doi.org/10.1016/j.ddtec.2012.10.012.

Journal Pre-proof
[3]
W. H. Moos, C. R. Hurt, Morales, G. A. Combinatorial chemistry: oh what a decade or two
can do. Mol. Diversity. 13 (2009) 241-245. https://doi.org/10.1007/s11030-009-9127-y
4] B. B. Tour, D. G. Hall, Chem. Rev. 109 (2009) 4439-4486. https://doi.org/
0.1021/cr800296p.
[
1
[5]
C. Lamberth. Multicomponent reactions in crop protection chemistry. Bioorg. Med. Chem.
2
8 (2020) 115471. https://doi.org/10.1016/j.bmc.2020.115471.
[6]
R. Kakuchi, Multicomponent Reactions in Polymer Synthesis. Angew. Chem. Int. Ed. 53
(
2014) 46-48. https://doi.org/ 10.1002/anie.201305538.
[7]
8]
M. B. A. Gloria, Encyclopedia of Food Sciences and nutrion. Second Edition. 2003, 173.
D. E Edmondson, A Mattevi, C Binda, M Li, F. Hubálek, Structure and mechanism of
[
monoamine oxidase. Curr Med Chem. 11 (2004) 1983-1993. https://doi.org/
0.2174/0929867043364784.
1
[9]
M. Pagliaro, S. Campestrini, R. Ciriminna, Ru-based oxidation catalysis. Chem. Soc. Rev.
34 (2005) 837-845. https://doi.org/10.1039/B507094P.
[
10] J. H. Teles, I. Hermans, G. Franz, R. A. Sheldon, Wiley-VCH Verlag GmbH & Co. KGaA,
Weinheim, 2015, DOI: 10.1002/14356007.a18_261.pub.
11] U. R. Pillai, E. Sahle-Demessie, Oxidation of alcohols over Fe3+/montmorillonite-K10
using hydrogen peroxide Appl. Catal. Gen. 245 (2003) 103-109.
https://doi.org/10.1016/S0926-860X(02)00617-8.
12] I. E. Marko, P. R. Giles, M. Tsukazaki, I. Che´lle-Regnaut, A. Gautier, M. S. Brown, C. J. Urch,
Efficient, Ecologically Benign, Aerobic Oxidation of Alcohols. J. Org. Chem. 64 (1999) 2433-
439. https://doi.org/10.1021/jo982239s.
13] M.; Gupta, Paul, S.; Gupta, R. General aspects of 12 basic principles of green chemistry
with applications. Curr. Sci. 99 (2010) 1341-1360. https://www.jstor.org/stable/i24069032.
14] J. Dong, E. Fernández‐Fueyo, F. Hollmann, C. E. Paul, M. Pesic, S. Schmidt, Y. Wang, S
[
[
2
[
[
Younes, W. Zhang, Biocatalytic Oxidation Reactions: A Chemist's Perspective. Angew. Chem. Int.
Ed. 57 (2018) 9238-9261. https://doi.org/10.1002/anie.201800343.
[
15] M. Largeron, Aerobic catalytic systems inspired by copper amine oxidases: recent
developments and synthetic applications. Org. Biomol. Chem. 15 (2017) 4722-4730.
https://doi.org/10.1039/C7OB00507E.
[
16] A. Yoshida, Y. Takenaka, H. Tamaki, I. Frefibort, O. Adachi, H. J. Kumagai, Vanillin
formation by microbial amine oxidases from vanillylamine. J. Ferment. Bioeng. 84 (1997) 603-
05. https://doi.org/10.1016/S0922-338X(97)81920-4.
17] H. Priefert, J. Rabenhorst, Steinbüchel, Appl Microbiol Biotechnol. 56 (2001) 296-314.
https://doi.org/10.1007/s002530100687.
18] V. L. Davidson, Electron transfer in quinoproteins. Arch. Biochem. Biophys. 428 (2004)
2-40. https://doi.org/ 10.1016/j.abb.2004.03.022.
19] G. Golime, G. Bogonda, , H. Y. Kim, K. Oh, Biomimetic Oxidative Deamination Catalysis via
6
[
[
3
[
ortho-Naphthoquinone-Catalyzed Aerobic Oxidation Strategy. ACS Catal. 8 (2018) 4986-4990.
https://doi.org/ 10.1021/acscatal.8b00992.
[20] R. Hilger, J.-P. Vincken, H. Gruppen, M. A. Kabel, Laccase/Mediator Systems: Their
Reactivity toward Phenolic Lignin Structures. ACS Sustainable Chem. Eng. 6 (2018) 2037-2046.
https://doi.org/ 10.1021/acssuschemeng.7b03451.
[
21] P. Galletti, F. Funiciello, R. Soldati, D. Giacominia, Selective Oxidation of Amines to
Aldehydes or Imines using Laccase‐Mediated Bio‐Oxidation. Adv. Synth. Catal. 357 (2015)
840-1848. https://doi.org/10.1002/adsc.201500165.
22] M. Ghandi, M. T. Nazeri, M. Kubicki, An efficient one-pot, regio- and stereoselective
synthesis of novel pentacyclic-fused pyrano[3,2,c]chromenone or quinolinone benzosultone
derivatives in water. Tetrahedron. 69 (2013) 4979-4989. https://doi.org/
0.1016/j.tet.2013.04.018.
23] P. Klumphu, B.H. Lipshutz, “Nok”: A Phytosterol-Based Amphiphile Enabling Transition-
1
[
1
[
Metal-Catalyzed Couplings in Water at Room Temperature. J. Org. Chem. 79 (2014) 888-900.
https://doi.org/ 10.1021/jo401744b.

Journal Pre-proof
[24] J. Gante, Peptidomimetics-Tailored Enzyme Inhibitors. Angew. Chem. Int.Ed. 33 (1994)
1
7, 1699-1720. https://doi.org/10.1002/anie.199416991.
25] A. Domling, W. Wang, K. Wang, Chemistry and Biology Of Multicomponent Reactions.
Chem. Rev. 112 (2012) 3083-3135. https://doi.org/ 10.1021/cr100233r.
26] D. Paprocki, D. Koszelewski, P. Walde, R.Ostaszewski, Efficient Passerini reactions in an
aqueous vesicle system. RSC Adv. (2015) 102828-102835. https://doi.org/
0.1039/C5RA22258C.
27] T. Ngouansavanh, J. Zhu, Alcohols in Isonitrile‐Based Multicomponent Reaction:
Passerini Reaction of Alcohols in the Presence of O‐Iodoxybenzoic Acid. Angew. Chem. Int. Ed,
5 (2006) 3495-3497. https://doi.org/ 10.1002/anie.200600588.
28] D. Paprocki, D. Koszelewski, A. Żądło, P. Walde, R. Ostaszewski, Environmentally
friendly approach to α-acyloxy carboxamides via a chemoenzymatic cascade. RSC Adv. 2016, 6,
8231-68237. https://doi.org/10.1039/C6RA13078J.
29] K. Singh, A. Kaur, V. S. Mithu, S. Sharma, Metal-Free Organocatalytic Oxidative Ugi
Reaction Promoted by Hypervalent Iodine. J Org Chem. 82 (2017) 5285-5293. https://doi.org/
0.1021/acs.joc.7b00594.
30] D. Paprocki, M. Wilk, A. Madej, P. Walde, R. Ostaszewski, Catalyst-free synthesis of α-
acyloxycarboxamides in aqueous media. Environ Chem Lett. 17 (2019)
https://doi.org/10.1007/s10311-018-0797-5.
31] M. J. Han, H. T. Choi, H. G. J. Song, Purification and characterization of laccase from the
white rot fungus Trametes versicolor. Microbiol. 43 (2005) 555-560.
32] L. A. Beaudette, O. P. Ward, M. A. Pickard, P. M. Fedorak, Low surfactant concentration
[
[
5
1
[
4
[
6
[
1
[
[
[
increases fungal mineralization of a polychlorinated biphenyl congener but has no effect on
overall metabolism. Lett. Appl. Microbial, 30 (2000) 155-160. https://doi.org/ 10.1046/j.1472-
7
[
65x.2000.00700.x.
33] J. Michizoe, H. Ichinose, N. Kamiya, T. Maruyama, M. Goto, Biodegradation of phenolic
environmental pollutants by a surfactant-laccase complex in organic media. J. Biosci. Bioeng.,
9 (2005) 642-647. https://doi.org/ 10.1263/jbb.99.642.
34] P.-P. Champagne, M. E. Nesheim, J. A. Ramsay, Effect of a non-ionic surfactant, Merpol,
on dye decolorization of Reactive blue 19 by laccase. Enzyme and Microbial Technology, 2010,
6, 147-152. https://doi.org/ 10.1016/j.enzmictec.2009.10.006.
9
[
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Prof. Ryszard Ostaszewski
Institute of Organic Chemistry, PAS
Kasprzaka 44/52
0
1-224 Warsaw, Poland
E-mail: ryszard.ostaszewski@icho.edu.pl
Dear Sir/Madam,
We are submitting CRediT author statement for manuscript entitled „ The amine as carbonyl precursor
in the chemoenzymatic synthesis of Passerini adducts in aqueous medium” CATCOM-D-20-00271R2.
Arleta Madej: Investigation, Chemical experiments, Enzymatic experiments, Writing- Original draft
preparation, Visualization,
Dominik Koszelewski; Investigation, Data curation
Daniel Paprocki: Investigation,
Anna Brodzka: Language corrections, editing
Ryszard Ostaszewski: Corresponding author, Supervision, Conceptualization, editing, submission of
manuscript.
Yours sincerely,
Ryszard Ostaszewski

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Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐
The authors declare the following financial interests/personal relationships which may be considered as
potential competing interests:
Ryszard Ostaszewski for manuscript entitled „The amine as carbonyl precursor in the
chemoenzymatic synthesis of Passerini adducts in aqueous medium”
Ref. No.: CATCOM-D-20-00271R2.

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Highlights
A new environmentally friendly method for the synthesis of α-acyloxy carboxyamides
was evaluated.
It consists sequential enzymatic oxidation of amines into aldehydes followed by Passerini
reaction.
A tandem one pot - two step protocol was elaborated.
For the first time chemoselective Passerini reaction was achieved.