Синтез оптично чистих 3-гетероарил-2-метилпропанових та 3-гетероарилбутанових кислот методом біокаталітичного розділення
A new approach has been developed for synthesizing compounds with potential biological activity − enantiomerically pure 3-heteroaryl-2-methylpropanoic and 3-heteroarylbutanoic acids. The enzymatic dynamic kinetic enzymatic resolution methodology was applied at key synthesis stages. A dual biocatalyt...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2025
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| author | Kolodiazhna, Anastasiia O. Faiziiev, Oleh O. Prysiazhnuk, Dmytro V. |
| author_facet | Kolodiazhna, Anastasiia O. Faiziiev, Oleh O. Prysiazhnuk, Dmytro V. |
| author_institution_txt_mv | [
{
"author": "Anastasiia O. Kolodiazhna",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Oleh O. Faiziiev",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Dmytro V. Prysiazhnuk",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Kolodiazhna, Anastasiia O. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:55Z |
| description | A new approach has been developed for synthesizing compounds with potential biological activity − enantiomerically pure 3-heteroaryl-2-methylpropanoic and 3-heteroarylbutanoic acids. The enzymatic dynamic kinetic enzymatic resolution methodology was applied at key synthesis stages. A dual biocatalytic purification method was employed to achieve a high degree of optical purity of the obtained products. The resulting amines are promising building blocks for the development of new pharmaceuticals and biologically active compounds |
| doi_str_mv | 10.15407/bioorganica2025.01.026 |
| first_indexed | 2025-07-17T12:20:09Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 1
UDC 661.741+547.293/.294
DOI: https://doi.org/10.15407/bioorganica2025.01.026
26
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
RESEARCH ARTICLE
Synthesis of optically pure 3-heteroaryl-2-methylpropanoic and
3-heteroarylbutanoic acids by biocatalytic resolution
Anastasiia O. Kolodiazhna*, Oleh O. Faiziiev, Dmytro V. Prysiazhnuk
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: A new approach has been developed for synthesizing compounds with potential biological activity − enantiomerically pure
3-heteroaryl-2-methylpropanoic and 3-heteroarylbutanoic acids. The enzymatic dynamic kinetic enzymatic resolution methodology was
applied at key synthesis stages. A dual biocatalytic purification method was employed to achieve a high degree of optical purity of the
obtained products. The resulting amines are promising building blocks for the development of new pharmaceuticals and biologically active
compounds.
Keywords: biocatalysis; chiral heterocyclic compounds; chiral 3-heterylbutanoic acids; 3-heteryl-2-methylpropanoic acids; lipase;
enzymatic resolution; optical activity.
Introduction
Heterocyclic compounds play an extremely important
role in pharmacology, as they form the basis of many
pharmaceutical drugs. Approximately 75-90% of registered
pharmaceutical compounds contain heterocyclic structures
[1]. This is due to a range of properties and characteristics
of heterocyclic compounds, such as a broad spectrum of
biological activity, pharmacophoric nature, structural
diversity, the ability to enhance drug solubility, penetration
through biological membranes, and stability within the body
[2, 3]. Heterocyclic aliphatic carboxylic acids represent an
intriguing class of nitrogen-containing organic compounds
that exhibit diverse biological and pharmacological
activities. Among them there are important pharmaceutical
agents such as antibiotics, non-steroidal anti-inflammatory
drugs, antiviral agents, histamine antagonists, and GABA
inhibitors [4-7]. They can also be used as precursors in the
synthesis of many biologically significant compounds [8].
Received:
Revised:
Accepted:
Published online:
03.03.2025
24.03.2025
21.04.2025
30.06.2025
Corresponding author. Tel.: +380-50-870-4187;
e-mail: nastya_k11@ukr.net (A.O. Kolodiazhna)
ORCID: 0000-0002-7990-7830
In recent years, there has been a significant increase in
the use of chiral pharmaceutical agents. The regulatory
requirements on this matter were published by the US Food
and Drug Administration (FDA) as early as 1992 in a
document titled Development of New Stereoisomeric Drugs
[9, 10]. In accordance with these requirements, there has
been a substantial shift toward the development of
enantiomerically pure pharmaceuticals. As a result, the
demand for enantiomerically pure drugs is growing
annually by 13-15% [11, 12]. Therefore, the development
of new, simple, accessible, cost-effective, and
environmentally friendly methods for obtaining such
compounds remains a highly relevant task in modern
chemistry.
Chiral enantiomerically pure 3-heteroaryl-2-methylpro-
panoic acids and 3-heteroarylbutanoic acids are scarcely
described in the literature. In their racemic form, they have
been synthesized via the Horner-Wittig reaction, starting
from the corresponding heterocarbonyl compounds [13]. In
a stereochemically pure form, they were obtained through
asymmetric hydrogenation using chiral cobalt-based
catalysts, though the optical yields in this case remained
moderate [14].
In our work, we have developed a method for obtaining
stereochemically pure 3-heteroaryl-2-methylpropanoic
and 3-heteroarylbutanoic acids through enzymatic
kinetic resolution using lipases as biocatalysts.
© Kolodiazhna A.O. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
mailto:nastya_k11@ukr.net
A.O. Kolodiazhna et al.
27
Compound HetAr R1 R2
2a 2-Pyridine H CH3
2b 3-Pyridine H CH3
2c 4-Pyridine H CH3
2d 5-N-Me-Pyrazole H CH3
4a 3-Pyridine CH3 H
4b 4-Pyridine CH3 H
Scheme 1. Synthesis of racemic esters of 3-heteroarylbutanoic acids and 3-heteroaryl-2-methylpropanoic acids.
Results and Discussion
At the first stage of our work, racemic esters of
3-heteroaryl-2-methylpropanoic and 3-heteroarylbutanoic
acids (2a-e and 4a-b) were synthesized. To obtain them, we
employed the approach previously described by us [15],
following the two-step procedure shown in Figure 1.
Compound (R)-Ester Compound (S)-Acid Ea
HetAr Yield,% ee, % Yield,% ee, %
2a 2-Pyridine 40 97 5a 38 >100
2b 3-Pyridine 41 100 5b 40 100 >100
2c 4-Pyridine 38 97.5 5c 45 100 >100
2d 5-N-Me-Pyrazole 35 100 5d 37 100 >100
4a 3-Pyridine 39 100 6a 42 100 >100
4b 4-Pyridine 40 99 6b 40 97.5 >100
Scheme 2. Biocatalytic enantioselective resolution of heterocyclic carboxylic acid esters.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 1
28
Scheme 3. Acid hydrolysis of (R)-heterocarboxylic acid esters.
Thus, by applying the Horner-Wittig reaction at a key
stage, unsaturated heterocyclic carboxylic acids 1a-d and
3a-b were obtained from the corresponding substituted
heterocyclic carbonyl compounds and ethyl 2-(diethoxy-
phosphoryl)acetate. These intermediates were then hydro-
genated in the presence of palladium hydroxide. As a result,
racemic 3-heteroarylbutanoic acids 2a-e and 3-heteroaryl-2-
methylpropanoic acids 4a-b were obtained in approximately
90% yields and were used in further transformations
without additional purification.
The next stage involved obtaining enantiomerically pure
isomers of heterylcarboxylic acids. To achieve this,
enzymatic kinetic resolution was employed using lipases as
biocatalysts. A selection of highly efficient and highly
selective enzymes was tested, including lipases from
Burkholderia cepacia (Amano PS), Pseudomonas cepacia,
and Candida antarctica lipase B (CalB). Among these,
Amano PS lipase proved to be the most effective in
hydrolyzing racemic esters of heterocarboxylic acids.
The enzymatic hydrolysis was carried out in an aqueous
medium using a phosphate buffer at pH 7.0 with Amano PS
lipase [15-17]. All enantiomers of 3-heteryl-butanoic acids
(2a-d) and 3-heteryl-2-methylpropanoic acids as (R)-esters
(2a-d, 4a-b) and (S)-acids (5a-d, 6a-b) were obtained with
yields of 52-60% and enantiomeric purity of 97-100%
(Figure 2).
Table 1. 3-Phenylbutanoic acids and methyl-3-phenylpropanoic acids.
п/п Compound Optical Rotatory Power HPLC
ee, % [α]D
20 C (g/100 mL),
solvent
τ (R)
(min.)
τ (S)
(min.)
Conditions
1 (R)-5a 97 -14.86 0.5, MeOH 12.362 9.606 a
2 (S)-5a 97.5 +15.36 0.5, MeOH 12,081 9.656 a
3 (R)-5b 100 -30.91 0.5, MeOH 12.682 - b
4 (S)-5b 100 +32.36 0.5, MeOH - 17.407 b
5 (R)-5c 97.5 -26.95 0.5, MeOH 7.465 6.278 c
6 (S)-5c 100 +29.97 0.5, MeOH - 6.852 c
7 (R)-5d 100 -3.17 0.5, MeOH 17.947 - d
8 (S)-5d 100 +2.22 0.5, MeOH - 16.531 d
13 (S)-6a 100 -38.71 0.5, CH2Cl2 47.881 - e
14 (R)-6a 100 +38.18 0.5, CH2Cl2 41.411 e
15 (S)-6b 97.5 -28.26 0.5, CHCl3 4,071 3.615 f
16 (R)-6b 99 +28.46 0.5, CHCl3 - 3.442 f
Conditions: а) Column: Chiralpak AD-H (250 × 4.6 mm, 5 mkm) -3; Mobile Phase : Hexane : IPA : MeOH, 50:25:25; Flow Rate, 0.6 mL/min. b) Column:
Chiralcel OJ-H (250 × 4.6 mm, 5 mkm) -3; Mobile Phase: Hexane (0.1%TFA) : IPA : MeOH, 70:15:15; Flow Rate, 0.6 mL/min. c) Column: Chiralpak AD-
H (250 × 4.6 mm, 5 mkm -3; Mobile Phase: CO2 : MeOH, 90:10; Flow Rate, 2.0 mL/min. d) Column: Chiralpak AD-H (250 × 4.6 mm, 5 mkm) - Mobile
Phase: Hexane (0.1% TFA) : IPA, 90:10; Flow Rate, 0.6 mL/min. e) Column: Chiralcel OJ-H (250 × 4.6 mm, 5 mkm) - OJH0CE-UF008-3; Mobile Phase:
Hexane (0.1%TFA) : IPA (0.1%TFA) : MeOH (0.1%TFA), 90:5:5; Flow Rate, 0.6 mL/min. f) Column: Chiralpak AD-H (250 × 4.6 mm, 5 mkm) -3;
Mobile Phase: CO2 : MeOH, 80:20 ; Flow Rate, 2.0 mL/min.
A.O. Kolodiazhna et al.
29
Next, the obtained (R)-esters 2a-d and 4a-b were
subjected to acidic hydrolysis by heating ap to 40 °C for 3
days in deionized water in the presence Novozyme 435,
yielding good, quantitative results without the need for
additional purification (Figure 3). In all cases, the
hydrolysis proceeded without racemization, preserving the
absolute configuration of the compounds. As a result, all
stereoisomers of 3-heteroarylbutanoic acids 5a-d and
3-heteroaryl-2-methylpropanoic acids 6a-b were obtained.
They were characterized using available physicochemical
methods (Table 1).
Conclusions
In this work, we obtained and described all optical
isomers of 3-heteroarylbutanoic and 3-heteroaryl-2-
methylpropanoic acids. For this purpose, a method of
biocatalytic kinetic resolution of racemates of the esters of
these acids was employed. Different lipases were used as
biocatalysts, namely Burkholderia cepacia Amano PS
lipase, Pseudomonas cepacia lipase, and Candida
antarctica lipase B. The most effective lipase for the
enzymatic hydrolysis of the esters of these acids was found
to be Amano PS lipase. All optically active hetero-
carboxylic acids were obtained with high chemical yields,
optical purity >95%, and the preservation of the absolute
configuration of the chiral center. These compounds were
described and characterized using modern physicochemical
methods.
Experimental section
All solvents were purified according to standard
procedures. All starting materials were obtained from
Enamine LTD. or other commercial sources. Melting points
were measured using the MPA 100 OptiMelt, an automated
melting point determination system. 1H and 13C NMR
spectra were recorded in CDCl3 on a Bruker Avance III 500
MHz spectrometer (Germany) at ambient temperature.
Chemical shifts (δ) are given in parts per million relative to
tetramethylsilane (TMS) as the internal standard. Signal
multiplicity is shown as s (singlet), d (doublet), dd (doublet
of doublets), t (triplet), m (multiplet), br (broad signal), q
(quartet). Spin-spin coupling constants (J) are given in
Hertz. Chiral HPLC analysis was carried out on an Agilent
1100 chromatographic system equipped with a Chiralpak
OD-3 column or Chiracel analytical columns (Chiral
Technologies) with a cellulose-based stationary phase. All
reagents and solvents were used without further
purification. Column chromatography was performed on
silica gel 60 (70-230 mesh). Optical rotation was measured
using a Perkin-Elmer polarimeter model 241 (sodium D line
at 20 °C). Melting temperatures were not corrected. All
reactions were carried out in glassware that was dried by
flame or in a drying oven. Burkholderia cepacia lipase
(Amano PS), Pseudomonas cepacia lipase from Amano
Pharmaceutical (Japan), and Candida antarctica lipase B
from Novozymes A/S (Denmark) were used. The progress
of reactions was monitored by analytical thin-layer
chromatography (TLC) on silica gel 60F254 plates (Merck,
Germany), and products were visualized using anisaldehyde
or UV light. The purity of all compounds was determined
using TLC and NMR measurements.
Synthesis
General Method for the Synthesis of (R) and (S)
3-heteroaryl-2-methylpropanoic and 3-heteroarylbutanoic
acids 5a-d and 6a-b.
A solution of 0.25 mol of racemic heteroarylcarboxylic
acid ester 2a-d or 4a-b in 1500 mL of phosphate buffer
pH 7.0. Add 20 g of Amano PS lipase. The mixture was
stirred for 16 h at room temperature and then filtered. The
filtrate was acidified with 2 M HCl to pH 2 and extracted
with MTBE (3 × 300 mL). The organic extract was washed
with 0.2 M aqueous potassium carbonate solution (2 × 300
mL), dried with sodium sulfate, and evaporated in a
vacuum. (R)-Heteroarylcarboxylic acid esters 2a-d or 4a-b
were obtained. Yield 38-41%; 93-100% ee. After ex-
traction, the aqueous solution was acidified with 2 M HCl
to a pH of 2, and then extracted with MTBE (3 × 500 mL).
The extract was washed with sodium chloride solution,
dried with sodium sulfate, and evaporated in a vacuum.
(S)-Arylcarboxylic acids 5a-d or 6a-b were obtained. Yield
35-42%, 97-99% ee. To a 0.1 M solution of the correspond-
ding enantiomerically pure (R)-heteroarylcarboxylic acid
esters 2a-d or 4a-b (0.1 mol) in distilled water Novozyme
435 (0.1 g) was added in one portion. The mixture was
heated to 40 °C and stirred at this temperature for 3 days.
The mixture was filtered and concentrated. The residue was
triturated in MTBE. The (R)-heteroarylcarboxylic acids 5a-
d or 6a-b were obtained as a white powder. Yield 75-90%,
97-99% ee.
(R)-Ethyl 3-(pyridin-2-yl)butanoate (2a).
Pale yellow oil; yield 40%. 1H NMR (СDCl3, 500 MHz)
8.54-8.53 (d, J = 6.0 Hz, 1H), 7.62-7.58 (t, J = 9.5 Hz,
1H), 7.20-7.10 (dd, J = 37.5, 9.5 Hz, 1H), 4.10-4.04 (q, J =
8.5 Hz, 2H), 3.46-3.37 (m, 1H), 2.90-2.57 (dq, J = 138.5,
9.0 Hz, 2H), 1.35-1.33 (d, J = 8.5 Hz, 3H), 1.20-1.16 (t, J =
9.0, 3H).
(R)-Ethyl 3-(pyridin-3-yl)butanoate (2b).
Pale yellow oil; yield 41%. 1H NMR (DMSO-d6,
500 MHz) 8.90-8.89 (d, J = 2.0 Hz, 1H), 8.77-8.76 (d,
J = 7.0 Hz, 1H), 8.56-8.54 (d, J = 10.0 Hz, 1H), 8.01-7.97
(dd, J = 10.0, 7.0, Hz, 1H), 4.02-3.94 (m, 2H), 3.47-3.38
(m, 1H), 2.84-2.73 (m, 1H), 1.29-1.28 (d, J = 8.5 Hz, 3H),
1.10-1.07 (t, J = 9.5 Hz, 3H).
(R)-Ethyl 3-(pyridin-4-yl)butanoate (2c).
Pale yellow oil; yield 38%. 1H NMR (DMSO-d6,
500 MHz) 8.83-8.81 (d, J = 7.0 Hz, 2H), 8.00-7.99 (d, J =
7.5 Hz, 2H), 4.03-3.97 (m, 2H), 3.49-3.43 (m, 1H), 2.87-
2.75 (m, 2H), 1.30-1.28 (d, J = 8.5 Hz, 3H), 1.13-1.09 (t,
J = 8.5 Hz, 3H).
(R)-Ethyl 3-(pyrazol-5-yl)butanoate (2d).
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 1
30
Pale yellow oil; yield 35%. 1H NMR (СDCl3, 500 MHz)
7.34 (s, 1H), 5.98 (s, 1H), 4.10-4.04 (q, J = 9.0 Hz, 2H),
3.82 (s, 3H), 3.38-3.29 (m, 1H), 2.62-2.47 (dq, J = 9.0 Hz,
2H), 1.25-1.23 (d, J = 8.5 Hz, 3H), 1.20-1.16 (t, J = 8.5 Hz,
3H).
(R)-Ethyl 2-methyl-3-(pyridin-3-yl)propanoate (4a).
Pale yellow oil; yield 39%. 1H NMR (СDCl3, 500 MHz)
8.457 (s, 2H), 7.53-7.51 (d, J = 9.5 Hz, 1H), 7.24-7.21 (m,
1H), 4.12-4.07 (m, 2H), 3.02-2.97 (m, 1H), 2.74-2.70 (m,
2H), 1.21-1.18 (m, 5H).
(R)-Ethyl 2-methyl-3-(pyridin-4-yl)propanoate (4b).
Pale yellow oil; yield 40%. 1H NMR (DMSO-d6, 500
MHz) 8.811 (s, 1H), 8.78-8.76 (d, J = 5.5 Hz, 1H), 8.43-
8.42 (d, J = 8.0 Hz, 1H), 7.98-7.95 (m, 1H), 4.01-3.97 (q,
J = 7.5 Hz, 2H), 3.06-2.97 (m, 3H), 1.09-1.06 (t, J = 7.0 Hz,
3H).
(3S)-3-(Pyridin-2-yl)butanoic acid (5a).
White solid; yield 41%; mp 89 °C. 1H NMR (СDCl3,
500 MHz) 8.50-8.47 (d, J = 4.5 Hz, 1H), 7.86-7.78 (t, J =
7.5 Hz, 1H), 7.32-7.29 (m, 2H), 3.38-3.32 (m, 1H), 2.94-
2.80 (m, 2H), 1.43-1.42 (d, J = 7.0, 3H).
(3R)-3-(Pyridin-2-yl)butanoic acid (5a).
White solid; yield 37%; mp 88 °C. 1H NMR (СDCl3, 500
MHz) 8.50-8.49 (d, J = 4.5 Hz, 1H), 7.86-7.78 (t, J = 7.5
Hz, 1H), 7.32-7.29 (m, 2H), 3.38-3.32 (m, 1H), 2.94-2.80
(m, 2H), 1.43-1.42 (d, J = 7.0, 3H).
(3S)-3-(Pyridin-3-yl)butanoic acid (5b).
White solid; yield 40%; mp 90 °C. 1H NMR (DMSO-d6,
500 MHz) 8.46 (s, 1H), 8.38-8.37 (d, J = 4.5 Hz, 1H),
7.68-7.66 (d, J = 7.5 Hz, 1H), 7.30-7.28 (m, 1H), 3.18-3.14
(m, 1H), 2.54-2.53 (m, 2H), 1.21-1.21 (d, J = 7.0 Hz, 3H).
(3R)-3-(Pyridin-3-yl)butanoic acid (5b).
White solid; yield 40%; mp 90 °C. 1H NMR (DMSO-d6,
500 MHz) 8.46 (s, 1H), 8.38-8.37 (d, J = 4.5 Hz, 1H),
7.68-7.66 (d, J = 7.5 Hz, 1H), 7.30-7.28 (m, 1H), 3.18-3.14
(m, 1H), 2.54-2.53 (m, 2H), 1.21-1.21 (d, J = 7.0 Hz, 3H).
(3S)-3-(Pyridin-4-yl)butanoic acid (5c).
White solid; yield 34%; mp 170 °C. 1H NMR (DMSO-
d6, 500 MHz) 8.44-8.43 (d, J = 6.0 Hz, 2H), 7.27-7.26 (d,
J = 6.0 Hz, 2H), 3.14-3.09 (m, 1H), 2.54-2.52 (m, 2H),
1.19-1.18 (d, J = 7.0 Hz, 3H).
(3R)-3-(Pyridin-4-yl)butanoic acid (5c).
White solid; yield 36%; mp 172 °C. 1H NMR (DMSO-
d6, 500 MHz) 8.44-8.43 (d, J = 6.0 Hz, 2H), 7.27-7.26 (d,
J = 6.0 Hz, 2H), 3.14-3.09 (m, 1H), 2.54-2.52 (m, 2H),
1.19-1.18 (d, J = 7.0 Hz, 3H).
(3S)-3-(1-Methyl-1H-pyrazol-5-yl)butanoic acid (5d).
Light yellow solid; yield 39%; mp 127 °C. 1H NMR
(СDCl3, 500 MHz) 7.407 (s, 1H), 6.06 (s,1H), 3.86 (s,
3H), 3.39-3.34 (m, 1H), 2.67-2.56 (m, 2H), 1.30-1.29 (d,
J = 7.0 Hz, 3H).
(3R)-3-(1-Methyl-1H-pyrazol-5-yl)butanoic acid (5d).
Light yellow solid; yield 40%; mp 127 °C. 1H NMR
(СDCl3, 500 MHz) 7.41 (s, 1H), 6.06 (s,1H), 3.86 (s, 3H),
3.39-3.34 (m, 1H), 2.70-2.56 (m, 2H), 1.30-1.29 (d, J = 7.0
Hz, 3H).
(2S)-2-Methyl-3-(pyridin-3-yl)propanoic acid (6a).
White solid; yield 41%; mp 88 °C. 1H NMR (DMSO-d6,
500 MHz) 12.21 (br s, 1H), 8.39 (s, 2H), 7.61-7.59 (d, J =
8.0 Hz, 1H), 7.29 (m, 1H), 2.89-2.83 (m, 1H), 2.68-2.62 (m,
2H), 1.04-1.03 (d, J = 7.0 Hz, 3H).
(2R)-2-Methyl-3-(pyridin-3-yl)propanoic acid (6a).
White solid; yield 42%; 89 °C. 1H NMR (DMSO-d6, 500
MHz) 12.21 (br s, 1H), 8.39 (s, 2H), 7.61-7.59 (d, J = 8.0
Hz, 1H), 7.29 (m, 1H), 2.89-2.83 (m, 1H), 2.68-2.62 (m,
2H), 1.04-1.03 (d, J = 7.0 Hz, 3H).
(2S)-2-Methyl-3-(pyridin-4-yl)propanoic acid (6b).
White solid; yield 38%; mp 160 °C. 1H NMR (DMSO-
d6, 500 MHz) 12.233 (br s, 1H),8.44-8.43 (d, J = 4.5 Hz,
2H), 7.21-7.20 (d, J = 4.0 Hz, 2H), 2.90-2.85 (m, 1H), 2.71-
2.61 (m, 2H), 1.04-1.03 (d, J = 7.0, 3H).
(2R)-2-Methyl-3-(pyridin-4-yl)propanoic acid (6b).
White solid; yield 42%; mp 160 °C. 1H NMR (DMSO-
d6, 500 MHz) 12.23 (br s, 1H), 8.44-8.43 (d, J = 4.5 Hz,
2H), 7.21-7.20 (d, J = 4.0 Hz, 2H), 2.90-2.85 (m, 1H), 2.71-
2.61 (m, 2H), 1.04-1.03 (d, J = 7.0, 3H).
Notes
Acknowledgments. We would like to thank Enamine
Ltd. for the material and technical support for the synthetic
part of this work. The authors thank all the brave defenders
of Ukraine who stood against the russian full-scale invasion
and made this publication possible.
The authors declare no conflict of interest.
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Синтез оптично чистих 3-гетероарил-2-метилпропанових та
3-гетероарилбутанових кислот методом біокаталітичного розділення
А.О. Колодяжна, О.О. Файзієв, Д.В. Присяжнюк.
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
Резюме: Розроблено новий підхід до синтезу сполук з потенційною біологічною активністю − енантіомерно чистих 3-гетероарил-2-
метилпропанових та 3-гетероарилбутанових кислот. На ключових етапах синтезу застосовано методологію ферментативного динамічного
кінетичного розділення. Для досягнення високого ступеня оптичної чистоти отриманих продуктів використано метод подвійного
біокаталітичного очищення. Отримані аміни є перспективними будівельними блоками для розробки нових фармацевтичних препаратів та
біологічно активних сполук.
Ключові слова: біокаталіз; хіральні гетероциклічні сполуки; хіральні 3-гетерилбутанові кислоти; 3-гетерил-2-метилпропанові кислоти; ліпаза;
ферментативне розділення; оптична активність.
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-new-stereoisomeric-drugs
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-new-stereoisomeric-drugs
|
| id | oai:ojs2.bioorganica.com.ua:article-97 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:39Z |
| publishDate | 2025 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/c5/7736a8319ec5ced6e3e153159ab904c5.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-972026-07-19T14:56:55Z Synthesis of optically pure 3-heteroaryl-2-methylpropanoic and 3-heteroarylbutanoic acids by biocatalytic resolution Синтез оптично чистих 3-гетероарил-2-метилпропанових та 3-гетероарилбутанових кислот методом біокаталітичного розділення Kolodiazhna, Anastasiia O. Faiziiev, Oleh O. Prysiazhnuk, Dmytro V. biocatalysis chiral heterocyclic compounds chiral 3-heterylbutanoic acids 3-heteryl-2-methylpropanoic acids lipase enzymatic resolution optical activity біокаталіз хіральні гетероциклічні сполуки хіральні 3-гетерилбутанові кислоти 3-гетерил-2-метилпропанові кислоти ліпаза ферментативне розділення оптична активність A new approach has been developed for synthesizing compounds with potential biological activity − enantiomerically pure 3-heteroaryl-2-methylpropanoic and 3-heteroarylbutanoic acids. The enzymatic dynamic kinetic enzymatic resolution methodology was applied at key synthesis stages. A dual biocatalytic purification method was employed to achieve a high degree of optical purity of the obtained products. The resulting amines are promising building blocks for the development of new pharmaceuticals and biologically active compounds Розроблено новий підхід до синтезу сполук з потенційною біологічною активністю − енантіомерно чистих 3-гетероарил-2-метилпропанових та 3-гетероарилбутанових кислот. На ключових етапах синтезу застосовано методологію ферментативного динамічного кінетичного розділення. Для досягнення високого ступеня оптичної чистоти отриманих продуктів використано метод подвійного біокаталітичного очищення. Отримані аміни є перспективними будівельними блоками для розробки нових фармацевтичних препаратів та біологічно активних сполук V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2025-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/97 10.15407/bioorganica2025.01.026 Ukrainica Bioorganica Acta; Vol. 20 No. 1 (2025): Ukrainica Bioorganica Acta; 26-31 Ukrainica Bioorganica Acta; Том 20 № 1 (2025): Ukrainica Bioorganica Acta; 26-31 1814-9766 1814-9758 10.15407/bioorganica2025.01 en https://bioorganica.com.ua/index.php/journal/article/view/97/98 Copyright (c) 2025 Anastasiia O. Kolodiazhna, Oleh O. Faiziiev, Dmytro V. Prysiazhnuk https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | біокаталіз хіральні гетероциклічні сполуки хіральні 3-гетерилбутанові кислоти 3-гетерил-2-метилпропанові кислоти ліпаза ферментативне розділення оптична активність Kolodiazhna, Anastasiia O. Faiziiev, Oleh O. Prysiazhnuk, Dmytro V. Синтез оптично чистих 3-гетероарил-2-метилпропанових та 3-гетероарилбутанових кислот методом біокаталітичного розділення |
| title | Синтез оптично чистих 3-гетероарил-2-метилпропанових та 3-гетероарилбутанових кислот методом біокаталітичного розділення |
| title_alt | Synthesis of optically pure 3-heteroaryl-2-methylpropanoic and 3-heteroarylbutanoic acids by biocatalytic resolution |
| title_full | Синтез оптично чистих 3-гетероарил-2-метилпропанових та 3-гетероарилбутанових кислот методом біокаталітичного розділення |
| title_fullStr | Синтез оптично чистих 3-гетероарил-2-метилпропанових та 3-гетероарилбутанових кислот методом біокаталітичного розділення |
| title_full_unstemmed | Синтез оптично чистих 3-гетероарил-2-метилпропанових та 3-гетероарилбутанових кислот методом біокаталітичного розділення |
| title_short | Синтез оптично чистих 3-гетероарил-2-метилпропанових та 3-гетероарилбутанових кислот методом біокаталітичного розділення |
| title_sort | синтез оптично чистих 3-гетероарил-2-метилпропанових та 3-гетероарилбутанових кислот методом біокаталітичного розділення |
| topic | біокаталіз хіральні гетероциклічні сполуки хіральні 3-гетерилбутанові кислоти 3-гетерил-2-метилпропанові кислоти ліпаза ферментативне розділення оптична активність |
| topic_facet | biocatalysis chiral heterocyclic compounds chiral 3-heterylbutanoic acids 3-heteryl-2-methylpropanoic acids lipase enzymatic resolution optical activity біокаталіз хіральні гетероциклічні сполуки хіральні 3-гетерилбутанові кислоти 3-гетерил-2-метилпропанові кислоти ліпаза ферментативне розділення оптична активність |
| url | https://bioorganica.com.ua/index.php/journal/article/view/97 |
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