Biocatalytic Promiscuity of Lipases in Carbon-Phosphorus Bond Formation

Article abstract of DOI:10.1002/cctc.201900397

A promiscuous lipase-catalyzed carbon-phosphorus bond formation is presented. The developed enzymatic Pudovik-Abramov reaction of various aromatic and aliphatic aldehydes with dialkyl phosphonates provides biologically and pharmacologically relevant α-hyd

Full text of DOI:10.1002/cctc.201900397

Accepted Article
Title: Biocatalytic promiscuity of lipases in carbon–phosphorus bond
formation
Authors: Dominik Koszelewski and Ryszard Ostaszewski
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ChemCatChem
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Biocatalytic promiscuity of lipases in carbon–phosphorus bond
formation
Dominik Koszelewski,* and Ryszard Ostaszewski
We would like to dedicate this paper to Professor Paweł Kafarski on occasion of his 70th birthday
Abstract: A promiscuous lipase-catalyzed carbon–phosphorus bond
formation is presented. The developed enzymatic Pudovik-Abramov
reaction of various aromatic and aliphatic aldehydes with dialkyl
phosphonates provides biologically and pharmacologically relevant α-
hydroxy phosphonates with the yields from 11% to 85%. The
developed protocol proceeds in the presence of porcine pancreas
lipase under environmentally sustainable conditions. The influence of
the reaction conditions including enzyme origin, organic solvent, and
temperature on the reaction course was examined. The developed
protocol is applicable to a range of aldehydes, including synthetically
relevant heterocyclic furfural and 2-thiophenecarbaldehyde.
numerous α-hydroxy phosphonates derivatives has been
established under various reaction conditions. These methods
comprising the application of Lewis acids and base catalysts such
as calcium oxide,[12] NbCl
,[13] aluminum(III) complex,[14]
5
amberlyst-15,[
Bi(NO x5H
RuClCp(PPh
15]
n-butyllithium,[16]
transition metal
Ti(O-i-Pri)
catalyst
,[17]
e.g.
4
)
3
2
O[18]
or
3
3
)
2
.[19] Unfortunately, many of reported protocols
suffer from some inconveniences such as stoichiometric amount
of catalysts, water free environment or application of expensive
and highly toxic transition metal catalysts. Thus, it seems
meaningful to find a method to overcome these limitations.
Moreover, due to pharmacopoeia guidelines the contaminations
of product with heavy metal must remain below 5 ppm what
significantly constricted application of reported methods in the
pharmaceutical industry. Recently, many efforts have been made
Introduction
to elaborate an environmentally sustainable protocol toward α-
α-Hydroxy phosphonates are considered as an important class of
organic compounds due to their agricultural and pharmaceutical
properties[1] and as suitable materials in the preparation of various
α, and γ substituted phosphonates.[2] α-Hydroxyalkyl phosphonic
acids and their esters are of great interest due to their interesting
biological activities such as antibacterial,[3] fungicidal,[4]
anticancer,[ angiotensinogenase and HIV inhibitory effects.[7]
For example, fosfomycin which was isolated from Streptomyces
fradiae exhibits antibiotic activity (Figure 1).[8]
[20]
hydroxy phosphonates.
Therefore, the development of new
synthetic protocols toward α-hydroxy phosphonates derivatives
which eliminate mentioned disadvantages remains desirable.
Although several methods regarding synthesis of α-hydroxy
phosphonates have been recently reported, none of them are
based on chemoenzymatic approaches. Due to exceptional low
environmental and physiological impact as well as high selectivity
5]
[6]
and mild reaction conditions enzymes were found to be also
[21,22]
attractive for industrial-scale synthesis
Moreover, a new
frontier, referred as biocatalytic promiscuity, has extensively
enlarged the application of enzymes.[23] Enzyme biocatalytic
promiscuity concerns the ability of an enzyme to promote
transformations differ from its natural activity profile. Recently we
have reported the enzyme-catalyzed Knoevenagel condensation
and Ugi-condensation.[24] Herein, as a part of our ongoing work
under sustainable protocols and promiscuous biocatalysis, we
report an enzyme-catalyzed carbon–phosphorus bond formation
via Pudovik-Abramov reaction.
Figure 1. Biologically active organophosphorus compounds.
The major synthetic route towards α-hydroxy phosphonate
derivatives embrace the base-catalyzed Pudovik reaction.[9,10] At
the same time Abramov reported an analogous addition of
Results and Discussion
Based on the literature premise on enzyme catalyzed aldol
reaction the model reaction of 4-nitrobenzaldehyde (1) (1 mmol)
and dimethyl phosphonate (2) (1 mmol) was conducted at 40 °C
for 96 hours in cyclohexane to screen the promiscuous catalytic
activity of various enzymes (Scheme 1).[ In the absence of
catalyst product 3a was isolated only with 3% after 96 h (Table 1,
entry 1).
organophosphorus
nucleophilic
partners
to
carbonyl
compounds.[11] A variety of methodologies for the synthesis of
25]
Dr. D. Koszelewski, Prof. R. Ostaszewski
Institute of Organic Chemistry
Polish Academy of Sciences
Kasprzaka 44/52, 01-224, Warsaw, Poland
E-mail: dominik.koszelewski@icho.edu.pl
https://ww2.icho.edu.pl/z20/
Supporting information available: H NMR, 13C NMR spectra.
1
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ChemCatChem
10.1002/cctc.201900397
FULL PAPER
and thermally denatured PPL were also applied. The results
indicated that BSA and denatured PPL only gave product 3a in
low yields (Table 1, entries 13 and 14). These results clearly show
that the peculiar active site of PPL is responsible for the Pudovik-
Abramov reaction. In addition three different non-enzymatic
catalysts reported in the literature; trimethylamine, aluminium
oxide and sodium carbonate were tested under similar reaction
conditions providing target product 3a with the yield up to 67%
Scheme 1. The Pudovik-Abramov reaction.
To find the most convenient biocatalyst more than 20 different
commercially available hydrolases and 1 domestic prepared pig
liver acetone powder were screened. The reactions were
terminated by enzyme separation and the crude product 3a was
purified by column chromatography (ethyl acetate/hexanes).
(
Table 1, entries 15-17).[20] Based on presented above results,
PPL was arbitrary selected and more efforts were taken to
improve overall procedure. To further optimize reaction conditions,
the impact of temperature (Table 1, entries 2,3 and 6) and enzyme
loading (Table 1, entries 3-5) on the PPL-catalyzed model
Pudovik-Abramov reaction were examined successively. The
enzyme loading exhibited an obvious influence on the yield and
the optimum catalytic amount was 100 mg of PPL (Table 1, entry
Table 1. The Pudovik-Abramov reaction catalyzed by different enzymes.[a]
Yield [%][f]
Entry
Catalyst
T [°C]
3), and the increase amount of biocatalyst change subtly the yield
1
2
3
4
5
6
7
8
9
None
40
30
40
40
40
50
40
40
40
40
40
40
40
40
40
40
40
3
of product 3a (Table 1, entry 5). To evaluate the effect of
temperature, the model reaction was carried out at a temperature
range from 30 °C to 50 °C. The reaction rate increased with
increasing temperature from 30 °C to 40 °C (Table 1, entries 2, 3
and 6); however the yield was significantly reduced above 40 °C
providing product 3a with 67% (Table 3, entry 6).
The progress of product 3a formation in enzyme catalyzed
reaction was also investigated (Figure 2). In less than 24 hours,
the target product 3a was obtained in moderate yield (25%) while
the yield did not increase substantially after 96 hour (82%).
Porcine pancreas lipase (PPL)
Porcine pancreas lipase
75
82
69
85
67
11
7
Porcine pancreas lipase[b]
Porcine pancreas lipase[c]
Porcine pancreas lipase
Candida cylindracea lipase (CCL)
Pseudomonas cepacia lipase (PCL)
Pseudomonas fluorescence lipase (PFL)
Candida rugosa lipase (CRL)
Novozym 435
13
18
4
10
11
12
13
14
15
16
17
Pig liver aceton powder (PLAP)[d]
Denatured PPL[e]
8
5
Bovine serum albumin (BSA)
Triethylamine
13
67
36
41
Aluminium oxide
Sodium carbonate
Figure 2. Time profile of 3a formation in the reaction catalyzed by PPL. Reaction
conditions: 4-nitrobenzaldehyde (1 mmol), dimethyl phosphonate (1 mmol),
cyclohexane (2 mL), 40 °C , 200 rpm, PPL (100 mg).
[
a] Reaction conditions: 4-nitrobenzaldehyde (1 mmol), dimethyl
phosphonate (1 mmol), and enzyme (100 mg) in cyclohexane (2 mL) for 96
h, 200 rpm. [b] PPL (80 mg), [c] PPL (120 mg), [d] Domestically prepared.
[
e] Thermally deactivated by refluxing in toluene for 24 h. [f] Yield of the
It is well recognized that the organic solvent considerably
may affect the enzyme activity.[27] Based on this fact eight
common used organic solvents were investigated (Table 2).
isolated product 3a after chromatography on silica gel.
As shown in Table 1, seven enzymes were found to promote
model reaction. The product 3a with the highest yield (82%) was
achieved using lipase from porcine pancreas (PPL) as a catalyst
Table 2. Effect of solvents on the Pudovik-Abramov reaction catalyzed by
PPL between 4-nitrobenzaldehyde and dimethyl phosphonate.[
a]
(
1
Table 1, entry 3), while other enzymes were less efficient (Table
, entries 7-12). In order to verify the promiscuous catalytic activity
of PPL in Pudovik-Abramov reaction, non-catalytic protein BSA[26]
Yield [%][c]
Entry
Solvent
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ChemCatChem
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FULL PAPER
1
2
3
4
5
6
7
8
9
Cyclohexane
82
52
<5
10
15
16
<1
<1
14
28
11
Cyclohexane[b]
2
H O
Acetonitrile
DMSO
DMF
t-Butanol
n-Propanol
Toluene
1,4-Dioxane
Neat
1
0
1
Figure 3. Recyclability of enzyme in 3a synthesis. Reaction conditions: 4-
nitrobenzaldehyde (1 mmol), dimethyl phosphonate (1 mmol) in cyclohexane (2
mL) for 96 h, 200 rpm at 40 °C.
1
[
a] Reaction conditions: 4-nitrobenzaldehyde (1 mmol), dimethyl
phosphonate (1 mmol), and enzyme (100 mg) in solvent (2 mL) for 96 h, 200
rpm at 40 °C. [b] H O (5% v/v). [c] Yield of the isolated product 3a after
To endorse this new protocol based on promiscuous activity
of PPL, we applied the developed reaction conditions using
aldehydes with various electron-withdrawing and electron-
donating groups. Obtained α-hydroxy phosphonates 3b-x are
shown in Figure 4.
2
chromatography on silica gel.
The results indicated that initially selected non-polar
cyclohexane was the most suitable medium for the studied
reaction (Table 2, entry 1), providing desired product 3b with 82%
yield. Application of polar protic and aprotic solvents significantly
reduced the yield of the desired product 3a (Table 1, entries 4-8
and 10). Similar adverse effect was observed for toluene (Table
2, entry 9). Subsequently, the influence of water on the course of
studied reaction was tested. It was shown that addition of 5% v/v
reduced the yield of product 3a to 52%, and the application of pure
water resulted only in traces of 3a (Table 2, entries 2 and 3). To
our delight, the α-hydroxy phosphonate 3a was also obtained in
11% yield under solvent-free conditions (Table 2, entry 11).
Obtained results revealed that the catalytic efficiency of PPL
significantly depends on the used solvent. Afterward, the
recycling of PPL was also examined. After each cycle the lipase
was recovered by filtration, washed with ethyl acetate, and reused.
There was gradual reduction in the yield of product 3a during the
third run whereas the yield declined up to 25% after the fourth run
(
Figure 3). The decreased activity of PPL over four reaction cycles
is largely due to mechanical loss of the enzyme upon each
separation step. Unfortunately, PPL only displayed low
stereoselectivity in studied reaction (ca. 5% ee; based on optical
rotation).
Figure 4. α-Hydroxy phosphonates obtained via enzyme catalyzed Pudovik-
Abramov reaction. Reaction conditions: aldehyde (1 mmol), dialkyl phosphonate
(1 mmol), and PPL (100 mg) in cyclohexane (2 mL) for 96 h, 200 rpm.
The application of aromatic aldehydes possessing a strong
electron-withdrawing group (such as nitro or cyano) resulted in α-
hydroxy phosphonates (3b-e) with better yields ranging from 68
to 52% (Figure 4), than aromatic aldehydes containing an
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ChemCatChem
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electron-donating group or a weak electron-withdrawing group,
such as, methyl, methoxy and halogenes, resulted in products 3f-
p moderate to good yields. This can be explain by the fact that
electron-withdrawing groups enhance the electrophilicity of
carbonyl carbon in aldehyde what enhances the reaction, while
electron-donating groups reduce it.[28] Moreover, the size of the
substituent attached to the ortho- and meta-position influence the
reactions yields, what may be explained by the dimension of the
biocatalyst’s active center. It is also important to notice that
slightly higher yields were obtained for the reaction performed
spectrometer (400 MHz). Chemical shifts are expressed in parts per million
using TMS as an internal standard. Mass spectra were recorded on API
3
65 mass spectrometer (SCIEX). Optical rotation was measured on Jasco
DIP-360 polarimeter. Elemental analysis was performed on Perkin Elmer
40 elemental analyzer. TLC analyses were done on Kieselgel 60 F254
aluminum sheets. Lipases from porcine pancreas, Type II (PPL)
catalogue number L-3126, Lot. number 108H1379), Pseudomonas
2
(
cepacia (PCL) (catalogue number 534641, Lot. number 03223JC),
Pseudomonas fluorescens (PFL) (catalogue number 534730, Lot. number
MKBH1198V), Candida rugosa (CRL) (catalogue number 90860, Lot.
number BCBH7102V), and Candida cylindracea (CCL) (catalogue number
62316, Lot. number 1336707) were purchased from Sigma-Aldrich.
with dimethyl than diethyl phosphonate what may pertain with
Immobilized lipase from Candida antarctica B (Novozym 435) (catalogue
number LC200223) was purchased from Novo Nordisk. Bovine serum
albumin were purchased from Sigma-Aldrich. Column chromatography
was performed on Merck silica gel 60/230-400 mesh. Enzymatic reactions
were performed in a vortex (Heidolph Promax 1020) equipped with
incubator (Heidolph Inkubator 1000). To validate the established protocol
each enzymatic transformation was triplicated.
29]
enzyme
substrate
selectivity.[
In
case
of
using
phenylacetaldehyde and 3-phenylpropanal the corresponding α-
hydroxy phosphonates 3q and 3r were obtained with 33% and
25% yields, respectively. Furfural, 2-thiophenecarbaldehyde as
well as acid sensitive unsaturated cinnamaldehyde were also
subjected to enzyme catalyzed Pudovik- Abramov reaction
providing corresponding products 3s-u with good yield without
polymerization in the presence of PPL. Finally, the reaction with
aliphatic aldehydes resulted in corresponding products 3v-x with
yields up to 25%, with the highest one for 3-methylbutanal.
Additional studies revealed that application of trimethylamine as
the catalyst under analogous reaction conditions resulted in 3v
with slightly enhanced yield (21%).
Preparation of crude liver powder (PLAP): Freshly purchased pig liver
(200 g) is homogenized twice in cold (-20 °C) acetone using kitchen stand
blender (24 000 rpm) equipped with glass jar. The mass obtained after
filtration was further homogenized twice in cold (-20 °C) DCM and filtrated.
The residue obtained was dried under vacuum at room temperature for 2
hours. Light brown powder (50 g) was stored in refrigerator before used.
General procedure for enzyme catalyzed Pudovik-Abramov reaction.
A mixture of an aldehyde (1 mmol), PPL (100 mg) and dialkyl phosphonate
(1 mmol) in cyclohexane (2 mL) was shaken at 200 rpm at 40 °C for 96
hours. Reaction was terminated by filtering off the catalyst. The residue
was washed with ethyl acetate. The combined organic phase was
concentrated under vacuum. The resulting residue was purified by column
chromatography (silica gel, eluent: ethyl acetate/hexanes, 9:1) to afford
the desired α-hydroxy phosphonates 3.
Conclusions
In summary, the promiscuous activity of lipases in carbon–
phosphorus bond formation via Pudovik-Abramov reaction of
various aliphatic and aromatic aldehydes with dialkyl
phosphonates was reported. Developed protocol signifies a new
biocatalytic way for the synthesis of α-hydroxy phosphonates
derivatives. The influences of reaction conditions, including
enzyme type, solvent, water content, enzyme loading, and
temperature, were investigated. The present method has several
advantages over protocols reported in the literature, including the
mild and green reaction conditions, simplicity, high-efficiency, and
good yield. In addition, the procedure offers minimal
environmental impact which makes it attractive pharmaceutical
industry. Moreover used biocatalyst was recovered and reused.
Using developed procedure three new α-hydroxy phosphonates
Dimethyl 1-hydroxy-2,4-dinitrophenylmethylphosphonate (3b): pale
1
yellow crystals; R
NMR (400 MHz, CDCl
Hz, 1H), 8.24 (dd, J = 8.7, 2.7 Hz, 1H), 6.38 (d, J = 15.3 Hz, 1H), 3.80 (d,
J = 10.8 Hz, 3H), 3.75 (d, J = 10.8 Hz, 3H); 13C NMR (100 MHz, CDCl
) δ
47.3 (s), 139.2 (s), 130.4 (d, J = 4.4 Hz), 127.3 (s), 120.1 (s), 66.6 (s),
5.0 (s), 55.0 (d, J = 7.4 Hz), 53.9 (d, J = 7.6 Hz); 31P NMR (162 MHz,
f
= 0.15 (ethyl acetate/hexanes, 9:1); m.p. 118-120 °C; H
3
) δ 8.85 (d, J = 1.5 Hz, 1H), 8.51 (dd, J = 8.7, 1.9
3
1
6
CDCl
3
) δ 20.3. Element. Anal. Calcd. for C
9
H
11
N
2
O
8
P C: 35.31%; H: 3.62;
+
N: 9.15%, found C: 35.18%; H: 3.49; N: 9.02%; HR ESIMS (M+Na) calcd
9 11 2 8
for C H N O P Na 329.0151, found 397.0148.
3b, 3e and 3k have been prepared which are now the subjects of
Dimethyl
1-hydroxy-2-nitro-4-dimethylaminophenylmethyl-
the ongoing biological studies. We believe that presented work
significantly expands the application of biocatalysts for
phosphonate (3e): orange crystals; R
m.p. 112-113 °C; H NMR (400 MHz, CDCl
f
= 0.13 (ethyl acetate/hexanes, 9:1);
) δ 7.78 (dd, J = 8.9, 2.3 Hz,
1
3
synthetically relevant carbon–phosphorus bond-forming reactions. 1H), 7.24 (d, J = 2.7 Hz, 1H), 6.97 (dd, J = 8.8, 2.7 Hz, 1H), 5.98 (d, J =
1
6
2.9 Hz, 1H), 3.79 (d, J = 10.6 Hz, 3H), 3.70 (d, J = 10.4 Hz, 3H), 3.05 (s,
Simple experimental procedure as well as environmentally
sustainable conditions allow us to believe that developed method
represents a profitable alternative to the existing protocols
reported in the literature.
H); 13C NMR (100 MHz, CDCl
3
) δ 150.1 (s), 129.7 (d, J = 4.7 Hz), 118.1
(
5
s), 116.4 (d, J = 2.7 Hz), 107.3 (s), 66.1 (s), 64.5 (s), 54.0 (d, J = 7.2 Hz),
3.6 (d, J = 7.2 Hz), 40.1 (s); 31P NMR (162 MHz, CDCl
3
) δ 23.4. Element.
Anal. Calcd. for C11
H
17
N
2
O
6
P C: 43.43%; H: 5.63; N: 9.21%, found C:
+
43.38%; H: 5.54; N: 9.18%; HR ESIMS (M+Na) calcd for C11
17 2 6
H N O PNa
327.0722, found 327.0719.
Experimental Section
Dimethyl 1-hydroxy-2,4-dimethoxyphenylmethylphosphonate (3k):
1
General methods. All the chemicals were obtained from commercial
sources and the solvents were of analytical grade. 1H- and 13CNMR
white crystals; R
f
= 0.17 (ethyl acetate/hexanes, 9:1); m.p. 112-113 °C; H
1
NMR (400 MHz, CDCl ) m.p. 97-98 °C;
3
H NMR (400 MHz, CDCl ) δ 7.46
3
spectra were recorded in CDCl
3
solution using Varian Gemini 400 NMR
(dd, J = 8.5, 2.3 Hz, 1H), 6.49 (dd, J = 8.5, 2.3 Hz, 1H), 6.44 – 6.34 (m,
H), 5.36 (d, J = 11.1 Hz, 1H), 4.19 (br. s, 1H), 3.77 (pseudo d, J = 10.2
1
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ChemCatChem
10.1002/cctc.201900397
FULL PAPER
Hz, 6H), 3.72 (d, J = 10.4 Hz, 3H), 3.59 (d, J = 10.3 Hz, 3H); 13C NMR (100
[13] V. Thottempudi, K.-H. Chung, Bull. Korean Chem. Soc. 2008, 29, 1781-
1783.
MHz, CDCl
.0 Hz), 117.4 (s), 104.8 (d, J = 2.3 Hz), 98.4 (d, J = 2.0 Hz), 65.3 (s), 63.7
s), 55.6 (s), 55.3 (s), 53.5 (dd, J = 12.7, 7.0 Hz); 31P NMR (162 MHz,
CDCl ) δ 24.8. Element. Anal. Calcd. for C11 P C: 47.83%; H: 6.20,
found C: 47.75%; H: 6.08; HR ESIMS (M+Na) calcd for C11 PNa
99.0660, found 299.0657.
3
) δ 160.8 (d, J = 2.8 Hz), 157.7 (d, J = 6.8 Hz), 129.5 (d, J =
5
(
[14] J. P. Abell, H. Yamamoto, J. Am. Chem. Soc. 2008, 130, 10521-10523.
[15] M. Tajbakhsh, A. Heydari, M. A. Khalizadeh, M. M. Lakouraj, B.
Zamenian, S. Khaksar, Synlett. 2007, 2347-2350.
[16] C. Liu, Y. Zhang, Q. Qian, D. Yuan, Y. Yao, Org. Lett. 2014, 16, 6172-
6175.
3
17 6
H O
+
17 6
H O
2
[
[
[
17] T. Yokomatsu, T. Yamagishi, S. Shibuya, J. Chem. Soc. Perkin Trans. I,
1997, 1527-1534.
18] A. Kumar, S. Jamwal, S. Khan, N. Singh, V. K. Rai, Phosphorus Sulfur
Silicon Rel. Elem. 2017, 192, 381-385.
Acknowledgements
19] I. R. Cabrita, P. R. Florindo, P. J. Costa, M. C. Oliveira, A. C. Fernandes,
Mol. Catal. 2018, 450, 77-86.
We gratefully acknowledge the financial support from the Polish
National Science Centre project OPUS No. 2016/B/ST5/03307.
[20] (a) Z. Rádai, G. Keglevich, Molecules 2018, 23, 1493; (b) T. Angelini, S.
Bonollo, D. Lanari, F. Pizzo, L. Vaccaro, Org. Biomol. Chem. 2013, 11,
5
042-5046; (c) G. Keglevich, V. R. Tóth, L. Drahos, Heteroatom Chem.
Keywords: Pudovik-Abramov reaction • α-hydroxy
phosphonates • promiscuity • hydrolases • biocatalysis
2011, 22, 15-17; (d) L. Xu, G. You, H. Peng, H. He, Phosphorus Sulfur
Silicon Rel. Elem. 2014, 189, 812-818; (e) L. Xu, G. You, H. Peng, H. He,
Phosphorus, Sulfur, and Silicon 2014, 189, 812-818.
[
1]
(a) N. S. Tulsi, A. M. Downey, C. W. Cairo, Bioorg. Med. Chem. 2010,
8, 8679-8686; (b) J. Desai, Y. Wang, K. Wang, S. R. Malwal, E. Oldfield,
[21] (a) M. D. Truppo, ACS Med. Chem. Lett. 2017, 8, 476-480; (b) U. T.
Bornscheuer, R. J. Kazlauskas, Hydrolases in Organic Synthesis: Regio
and Stereoselective Biotransformations, 2nd ed., Wiley-VCH, 2006; (c)
A. Liese, Industrial biotransformations, Wiley-VCH, 2000; (d) K. Faber,
Biotransformations in Organic Chemistry, Springer, 2011; (e) I. J. Colton,
D.L. (Tyler) Yin, P. Grochulski, R. J. Kazlauskas, Adv. Synth. Catal. 2011,
353, 2529-2544; (f) S. Guezane-Lakoud, M. Toffano, L. Aribi-Zouioueche,
Heteroatom Chem. 2017, e21408; (g) O. Pámies, J.-E. Bäckvall, J. Org.
Chem. 2003, 68, 4815-4818.
1
ChemMedChem 2016, 11, 2205-2215; (c) G. Jiang, D. Madan, G. D.
Prestwich, Bioorg. Med. Chem. Lett. 2011, 21, 5098-5101.
[2]
(a) L. Maier, Phosphorus, Sulfur and Silicon 1993, 76, 119-122; (b) E.
Öhler, S. Kotzinger, Synthesis 1993, 497-502; (c) R. Engel, Chem. Rev.
1
977, 77, 349-367.
R. U. Pokalwar, R. V. Hangarge, P. V. Maske, M. S. Shingare, ARKIVOC
006, (11), 196-204.
[3]
[4]
[5]
[6]
2
Y. Ishiguri, Y. Yamada, T. Kato, M. Sasaki, K. Mukai, Eur. Patent Appl.,
EP 82-301905, 1982; Chem. Abstr. 1983, 98, 102686u.
[22] A. Pellis, S. Cantone, C. Ebert, L. Gardossi, New Biotechnol. 2018, 40,
154-169.
R. M. N. Kalla, H. R. Lee, J. Cao, J.-W. Yoo, I. Kim, New J. Chem. 2015,
[23] (a) M. López-Iglesias, V. Gotor-Fernández, Chem. Rec. 2015, 15, 743-
759; (b) Y. Miao, M. Rahimi, E. M Geertsema, G. J. Poelarends, Curr.
Opin. Chem. Biol. 2015, 25, 115-123; (c) B. P. Dwivedee, S. Soni, M.
Sharma, J. Bhaumik, J. K. Laha, U. C. Banerjee, ChemistrySelect 2018,
3, 2441-2466; (d) X. Yu, B. Pérez, Z. Zhang, R. Gao Z. Guo, Green Chem.
2016, 18, 2753-2761; (e) M. Kapoor, A. B. Majumder, M. N. Gupta, Catal.
Lett. 2015, 145, 527-532; (f) U. K. Sharma, N. Sharma, R. Kumar, R.
Kumar, A. K. Sinha, Org. Lett. 2009, 11, 4846-4848; (g) F. Xu, J. Xu, Y.
Hu, X. Lin, Q. Wu, RSC Adv. 2016, 6, 76829-76837.
3
9, 3916-3922.
(a) D. V. Patel, K. Rielly-Gauvin, D. E. Ryono, Tetrahedron Lett. 1990,
1, 5587- 5590; (b) J. F. Dellaria Jr., R.G. Maki, H. H. Stein, J. Cohen, D.
3
Whittern, K. Marsh, D. J. Hoffman, J. J. Plattner, T. J. Perun, J. Med.
Chem. 1990, 33, 534-542.
[7]
(a) A. Szymańska, M. Szymczak, J. Boryski, J. Stawiński, A. Kraszewski,
G. Collu, G. Sanna, G. Giliberti, R. Loddo, P. La Colla, Bioorg. Med.
Chem. 2006, 14, 1924-1934; (b) A. Khandazhinskaya, E. Matyugina, E.
Shirokova, Expert Opin. Drug Metab. Toxicol. 2010, 6, 701-714.
B. G. Christensen, W. J. Leanza, T. R. Beattie, A. A. Patchett, B. H.
Arison, R. E. Ormond, F. A. Kuehl Jr., G. Albers-Schonberg, O. Jardetzky,
Science 1969, 166, 123-125.
[24] (a) D. Koszelewski, D. Paprocki, A. Madej, F. Borys, A. Brodzka, R.
Ostaszewski, Eur. J. Org. Chem. 2017, 4572-4579; (b) A. Żądło-
Dobrowolska, S. Kłossowski, D. Koszelewski, D. Paprocki, R.
Ostaszewski, J. Eur. Chem. 2016, 22, 16684-16689.
[
8]
9]
[
[
A. N. Pudovik, Doklady Akad. Nauk. SSSR, 1950, 73, 499-502; Chem.
Abstr. 1951, 45, 2856.
[25] C. Branneby, P. Carlqvist, A. Magnusson, K. Hult, T. Brinck, P. Berglund,
J. Am. Chem. Soc. 2003, 125, 874-875.
10] (a) V. M. Dembitsky, A. A. A. Al Quntar, A. Haj-Yehia, M. Srebnik, Org.
Chem. 2005, 2, 91; (b) C. Déjugnat, G. Etemad-Moghadam, I. Rico-
Lattes, Chem. Commun. 2003, 1858-1859; (c) Y. L. Xie, Q. Zhu, X. R.
Qin, Y. Y. Xie, Chin. Chem. Lett. 2003, 14, 25; (d) M. N. Dimukhametov,
E. V. Bayandina, E. Y. Davydova, A. T. Gubaidullin, I. A. Litvinov, V. A.
Alfonsov, Mendeleev Commun. 2003, 13, 150-151; (e) L. Tedeschi, D.
Enders, Org. Lett. 2001, 3, 3515-3517; (f) K. Vercruysse, C. Déjugnat, A.
Munoz, G. Etemad-Moghadam, Eur. J. Org. Chem. 2000, 281-289; (g)
D. B. Berkowitz, M. Bose, T. J. Pfannenstiel, T. Doukov, J. Org. Chem.
[26] (a) D. C. M. Albanese, N. Gaggero, RSC Adv. 2015, 5, 10588-10598; (b)
K. S. Dalal, Y. A. Tayade, Y. B. Wagh, D. R. Trivedi, D. S. Dalal, B. L.
Chaudhari, RSC Adv. 2016, 6, 14868-14879; (c) P. Ramesh, B. Shalini,
N. W. Fadnavis, RSC Adv. 2014, 4, 7368-7373; (d) N. Sharma, U. K.
Sharma, R. Kumar, N. Katoch, R. Kumar, A. K. Sinha, Adv. Synth. Catal.
2011, 353, 871-878; (e) Saima, D. Equbal, A. G. Lavekar, A. K. Sinha,
Org. Biomol. Chem. 2016, 14, 6111-6118.
[27] (a) A Zaks, A. M. Klibanov, PNAS 1985, 82, 3192-3196; (b) A. M.
Klibanov, Nature 2001, 409, 241-246.
2
000, 65, 4498-4508.
[28] R.-C. Tang, Z. Guan, Y.-H. He, W. Zhu, J. Mol. Catal. B: Enzym. 2010,
63, 62-67.
[
11] (a) V. S. Abramov, Doklady Akad. Nauk. SSSR 1950, 73, 487; Chem.
Abstr. 1951, 45, 2855; (b) V. I. Galkin, A. B. Khabibullina, I. V.
Bakhtiyarova, R. A. Cherkasov, A. N. Pudovik, Zh. Obsh. Khim. (Russ. J.
Gen. Chem.), 1990, 60, 92; (c) S. J. Chen, J. K. Coward, J. Org. Chem.
[29] G. Carrea, G. Ottolina, S. Riva, Trends Biotechnol. 1995, 13, 63-70.
1998, 63, 502-509; (d) O. Gawron, C. Grelecki, W. Reilly, J. Sands, J.
Am. Chem. Soc. 1953, 75, 3591-3592.
[12] G. Keglevich, V. Roza Toth, L. Drahos, Heteroatom Chem. 2007, 22,
226-229.
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ChemCatChem
10.1002/cctc.201900397
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Promiscuous lipase-catalyzed
Dominik Koszelewski* and Ryszard
Ostaszewski
carbon–phosphorus bond formation is
presented. The developed enzymatic
Pudovik-Abramov reaction of various
aromatic and aliphatic aldehydes and
dialkyl phosphonates provides
biologically and pharmacologically
relevant α-hydroxy phosphonates with
the yields up to 85%.
Page No. – Page No.
Biocatalytic promiscuity of lipases in
carbon–phosphorus bond formation
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