Біоміметичне трансамінування як загальний підхід до синтезу фторовмісних амінів та амінокислот
In this perspective review article, we describe the discovery of azomethine-azomethine isomerization of fluorinated N-benzyl-imines and its further development into one of the most convenient, scalable, and practical synthetic methods for preparation of biologically relevant fluorinated amines and a...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2023
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Ukrainica Bioorganica Acta| _version_ | 1871193597775183872 |
|---|---|
| author | Wzorek, Alicja Han, Jianlin Lyutenko, Nataliya V. Koley, Manankar Sorochinsky, Alexander E. Ono, Taizo Soloshonok, Vadim A. |
| author_facet | Wzorek, Alicja Han, Jianlin Lyutenko, Nataliya V. Koley, Manankar Sorochinsky, Alexander E. Ono, Taizo Soloshonok, Vadim A. |
| author_institution_txt_mv | [
{
"author": "Alicja Wzorek",
"institution": "Institute of Chemistry, Jan Kochanowski University in Kielce, Kielce, Poland"
},
{
"author": "Jianlin Han",
"institution": "College of Chemical Engineering, Nanjing Forestry University, Nanjing, China"
},
{
"author": "Nataliya V. Lyutenko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Manankar Koley",
"institution": "CSIR-Central Glass & Ceramic Research Institute, Kolkata, India"
},
{
"author": "Alexander E. Sorochinsky",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Taizo Ono",
"institution": "National Institute of Advanced Industrial Science and Technology (AIST), Anagahora, Shimoshidami, Moriyama-ku, Nagoya, Japan"
},
{
"author": "Vadim A. Soloshonok",
"institution": "University of the Basque Country, San Sebastián, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain "
}
] |
| author_sort | Wzorek, Alicja |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:54Z |
| description | In this perspective review article, we describe the discovery of azomethine-azomethine isomerization of fluorinated N-benzyl-imines and its further development into one of the most convenient, scalable, and practical synthetic methods for preparation of biologically relevant fluorinated amines and amino acids. Currently referred to as 1,3-Proton Shift Reaction, this method is widely used by organic chemists for synthesis of variety fluorinated amino compounds playing important role in the design of modern pharmaceuticals and agrochemicals |
| doi_str_mv | 10.15407/bioorganica2023.02.003 |
| first_indexed | 2025-07-17T12:19:55Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
UDC 547.233/.466.2
DOI: https://doi.org/10.15407/bioorganica2023.02.003
3
REVIEW
Discovery of biomimetic transamination as a general synthetic method
for preparation of fluorine-containing amines and amino acids
Alicja Wzorek1, Jianlin Han2, Nataliya V. Lyutenko3*, Manankar Koley4, Alexander E. Sorochinsky3,
Taizo Ono5, Vadim A. Soloshonok6,7
1 Institute of Chemistry, Jan Kochanowski University in Kielce, Kielce, Poland
2 College of Chemical Engineering, Nanjing Forestry University, Nanjing, China
3 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
4 CSIR-Central Glass & Ceramic Research Institute, Kolkata, India
5 National Institute of Advanced Industrial Science and Technology (AIST), Anagahora, Shimoshidami, Moriyama-ku, Nagoya, Japan
6 University of the Basque Country, San Sebastián, Spain
7 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
Abstract: In this perspective review article, we describe the discovery of azomethine-azomethine isomerization of fluorinated N-benzyl-
imines and its further development into one of the most convenient, scalable, and practical synthetic methods for preparation of
biologically relevant fluorinated amines and amino acids. Currently referred to as 1,3-Proton Shift Reaction, this method is widely used by
organic chemists for synthesis of variety fluorinated amino compounds playing important role in the design of modern pharmaceuticals
and agrochemicals.
Keywords: biomimetic reductive amination; fluorinated compounds; amines; α- and β-amino acids; drug design.
Introduction
In 1980s the spectacular future role of fluorine in drug
discovery has been far from obvious. Handful of fluorinated
pharmaceuticals on the market, such as fludrocortisone 1
[1] and 5-fluorouracil 2 [2] (Figure 1), were considered as a
mere curiosity since the extremely poisonous properties of a
few naturally occurring fluoroorganic compounds [3] were
very well known [4].
On the other hand, amino acids (AAs) are among the
most ubiquitous naturally occurring compounds and serve
numerous biological functions in living organisms [5].
Traditionally, naturally occurring and tailor-made
(synthetic) AAs are being quite frequently used in the
modern drug design [6, 7]. Clairvoyant or not, the decision
Received:
Revised:
Accepted:
Published online:
01.09.2023
12.10.2023
20.11.2023
30.12.2023
Corresponding author. Tel.: +380-44-573-2552;
e-mail: nlyutenko@bpci.kiev.ua (N.V. Lyutenko)
ORCID: 0000-0003-3538-2814
made by Academician V.P. Kukhar in the late 1980s to
initiate a new line of research targeting synthesis and bio-
evaluation of fluorine-containing AAs turn out to be one of
the most successful and prolific legacies of the Ukrainian
science of chemistry [8]. Nowadays, the introduction of
fluorine-containing substituents into the structure of a drug
candidate is a rapidly growing trend in the design of modern
drugs [9, 10]. Rational, selective fluorination allows for
fine-tuning of the targeted bioactivity and pharmaco-
kinetics. Over the last 20 years, fluorine scanning and
editing became rather standard steps in the design of new
drugs [9, 10]. Tailor-made fluorine-containing AAs are a
particularly exciting class of molecules widely used in drug
design [11]. Some of the most successful compounds
Figure 1. Structures of fludrocortisone 1 and 5-fluorouracil 2.
© Wzorek A. 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.
Ukrainica Bioorganica Acta
w w w.b io or gani c a.o rg .ua
mailto:nlyutenko@bpci.kiev.ua
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
4
3 4
N
O
Me
F
O
N
H
N
H
Me
CF3 NF3C
O
H
N
Me
O
N
NH
N
O
F F
F
Cl
Cl
O
NH2
N
H
F
5
COOEt
Figure 2. Recently approved drugs Avacopan (Tavneos™) 3, Atogepant (Qulipta™) 4 and Melflufen (Pepaxto™) 5.
recently introduced to the market are shown in Figure 2.
Avacopan (Tavneos™) 3 is an orally bioavailable highly
selective antagonist of human C5aR1 [12] was introduced
by ChemoCentryx. In 2021, Avacopan was approved by the
US FDA for the treatment of ANCA-associated vasculitis, a
rare form of autoimmune disease [13]. It contains fragments
of cyclic β-AA and two types of fluorination, aromatic F-
and CF3-groups. Atogepant (Qulipta™) 4 was developed by
AbbVie as an orally active and selective antagonist of the
calcitonin gene-related peptide (CGRP) receptors [14]. This
drug was approved, in 2021, by US FDA for the preventive
treatment of episodic migraines in adults [15]. Atogepant
contains substituted ornithine, in its lactam form, along with
aromatic (F) and aliphatic (CF3-CH2) fluorination motifs.
Melflufen (Pepaxto™) 5 is a dipeptide composed of two
tailor-made AA melphalan [16] and p-fluorophenylalanine.
It was developed by Oncopeptides for the treatment of
multiple myeloma and amyloid light-chain amyloidosis. In
2021 the US FDA approved Melflufen 5 in combination
with dexamethasone for the treatment of pre-treated adult
patients with relapsed or refractory multiple myeloma [17].
Biological transamination [18], is a primarily important
process in living organisms providing metabolic
interconversion of β-keto and α-amino acids (Scheme 1).
Mechanistically, biological transamination consists of a
base-catalyzed 1,3-proton transfer across the azaallyllic
anion intermediate 8 giving rise to Schiff bases of α-keto
acids 7 or α-amino acids 9 as precursors of α-amino acids
and pyridoxamine 10, and correspondingly, α-keto
carboxylic acids and pyridoxal 6 [19]. In a biological
system, the 1,3-proton transfer is catalyzed by the
enzymatic lysine omega-amino group which performs
enantio-selective proton transfer furnishing either 7 or 9 via
the delocalized 2-azaallyl anion 8 [20].
Numerous research groups, in particular, Breslow's [21],
Snell’s [19e], Martell’s [19a], Cram’s [22], and Casella’s
[23] studied the mechanism and stereochemistry of the
Scheme 1. Biochemical interconversion of α-amino and α-keto acids.
N.V. Lyutenko et al.
5
biological transamination using native as well as model
pyridoxal-based systems. They pointed out the importance
of the corresponding metal complex formation in
controlling the rate and stereochemistry of the
transamination process. Furthermore. it was demonstrated
that the 1,3-proton shift, in general, requires a strong base
for the isomerization to occur at a synthetically useful rate
[24]. Moreover, the equilibrium constants measured for the
reaction were found to be satisfactorily correlated by the
Hammett equation (r = 0.94) suggesting the formation of
delocalized azaallyllic anion intermediate of type 8,
stabilized by electron-withdrawing and correspondingly,
destabilized by electron-releasing substituents [25].
Biomimetic transamination. Non-fluorinated
substrates.
From a synthetic point of view, the biological
transamination is an intramolecular reduction-oxidation
process via base-catalyzed 1,3-proton shift in the azaallylic
system of the corresponding imine (Scheme 2). Obviously,
if there is a way to control the equilibrium between imines
13 and 15, then one can realize as biomimetic approach for
oxidation of amines 17 to carbonyl compounds 11, or
conversely, reductive amination of carbonyl compounds 11
to amines 17. To consider this biomimetic approach
synthetically useful, the equilibrium between 13 and 15
should show a clear preference for one of the compounds.
The obvious methodological advantage of this biomimetic
approach over traditional chemical reduction/oxidation
methods is that it does not require the use of external
oxidative or reducing reagents allowing for the
development of an environmentally benign, metal-free
reduction or oxidation processes [26].
Scheme 2. Biomimetic transamination of carbonyl compound 11
to amine 17 and vice versa.
First attempts to mimic the biological transamination
were reported by Professor’s Corey group who designed
highly electrophilic carbonyl compounds 18 and 19
(Scheme 3) and showed their application biomimetic
oxidative deamination of primary amines to the
corresponding ketones in high yields [26]. Calo et al.
reported that aldehyde 20 can be efficiently used for
oxidative deamination of some amines [27]. Various
reagents of type 21, mimicking natural pyridoxal 6, were
designed by Ohta's [28], Babler’s [29] and Rapoport’s [30]
groups, were shown to be of more general synthetic
application as they can be used for preparation of both
aldehydes and ketones.
NH2
C OReagent
O C NH2Reagent+
R
R
H
O
O
t-Bu
t-Bu NO2
O2N
O
O
O
X
X
O
18 19 20 21
X = C, N
Scheme 3. Synthetically useful reagents for biomimetic transami-
nation.
Examples of biomimetic reductive amination of carbonyl
compounds were reported by Cainelli [31], Kuzuhara [32],
Breslow [33], Zwanenburg [34], Berg [35], and others [36-
39].
In most of cases, benzhydryl aldimines 22, 23 (Scheme
4), possessing quite an acidic proton as well additional
stabilization of the product imine via the resonance, were
used as a source of hydrogen and nitrogen atoms.
Nevertheless, the application of strong bases, like KOtBu
was required to promote the biomimetic 1,3-proton shift
transfer. Application of this approach for transamination of
ketones was less successful, as compared to aldehydes,
except for electrophilic derivatives of αβ-dicarbonyl
compounds, and β-lactams.
NH2
Ar
Ar
O
R
R1
O
Ar
Ar
NH2
R
R1
+
NH2
NH2
S
O O
22 23
Scheme 4. Application of amines 22 and 23 for biomimetic
reductive amination of some carbonyl compounds.
Biomimetic transamination. Fluorinated
substrates.
The discovery of biomimetic reductive amination of
fluorinated carbonyl compounds dates to 1986 when Kuhar
group was trying to perform the Staudinger reaction
between keto-ester 24 and phosphazene 25 (Scheme 5) [40].
It was surprising to discover the formation of Schiff base 27
as a sole reaction product. By contrast, the reactions of the
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
6
corresponding N-alkyl or N-aryl phosphazenes in the place
of N-benzyl 25 gave the expected imine products of type 26
in high isolated yield [40c]. One can assume that the target
product 26 underwent in situ irreversible isomerization to
imine 27, catalyzed by the basic reagent 25. Product 27 was
easily hydrolyzed to yield trifluoroalanine 28 in high yield
[41].
24
25
F3C COOEt
O
N Ph
P
Ph Ph
Ph
26
F3C COOEt
N Ph
27
F3C COOEt
N Ph
28
F3C COOH
NH2
H
Scheme 5. Staudinger reaction followed by irreversible isome-
rization of 26 to 27.
Investigation of possible mechanistic details of the base-
catalyzed azomethine-azomethine isomerization of trifluo-
romethyl containing N-benzyl imines pointed to a nonionic
character of the corresponding intermediates, similar to 14
(Scheme 2) [42]. The role of a base, even as weak as
triethylamine, was suggested to increase the polarization of
one of the benzylic protons thus facilitating a concerted
1,3-proton shift transfer within a four-membered ring. [43].
Quite interesting, attempts to use this procedure for
chloro- or bromo-containing substrates were not successful.
In these cases, the expected dehydrohalogenation was the
major outcome of the reactions. For example, the 1,3-proton
shift in trichloromethyl imine 29 (Scheme 6) was followed
by the dehydrochlorination to yield compound 31 as a sole
isolated product [43]. Besides the difference in stability of
C-F and C-Cl bonds, this profound difference in the
outcome of the reactions of trifluoro- vs. trichloromethyl-
containing compounds can be additionally explained by
very specific steric [44] and electrostatic [45] effects of
trifluoromethyl group repulsing nucleophilic species and
thus protecting the imine products from the
dehydrochlorination.
31
Cl3C H
N Ph
30
Cl3C H
N Ph
29
Base Base H
N Ph
Cl
Cl
Scheme 6. Attempts to use chlorinated substrates in the
biomimetic reductive amination.
The unexpected outcome of the Staudinger reaction
(Scheme 5) was followed up by a systematic study of
isomerization of N-benzyl imines 33 (Scheme 7) derived
from various fluorinated aldehydes and ketones 32 [46].
Starting imines 33 can be quantitatively obtained by a direct
condensation of benzylamine and the corresponding
carbonyl compound using Dean-Stark conditions. It was
found that such a relatively weak base as triethylamine is
sufficiently active as a catalyst for the isomerization of 33
to Schiff bases 34. The observed reaction rates were
substantially faster for the aldehydes series as compared
with that of ketones, which can be rationalized by the lower
electrophilicity of the latter due to the electron-donating
effect of an alkyl group. In particular, in the case of
aldehydes, the isomerization of 33 to 34 takes place at
ambient temperature, while in the reaction of keto-
derivatives required slightly elevated temperatures (40-
50 ºC) for optimal reaction rates. As presented in Scheme 7,
carbonyl compounds containing difluoromethyl, trifluoro-
methyl, perfluoroalkyl, ω-hydro-perfluoroalkyl, and penta-
fluorophenyl groups were shown to be excellent substrates
for biomimetic transamination to the corresponding amines.
The triethylamine-catalyzed transformation of 33 to 34 is
virtually irreversible providing the latter in high chemical
yields (>85%). The resultant product 34 can be easily
hydrolyzed (1N HCl) to obtain target amines 35.
32
Rf R
N Ph
34
33
BaseRf R
O
H2N Ph
Rf R
N Ph
H Rf R
NH2
35
Rf = CHF2, CF3, C2F5, C3F9, C4F9, H(CF2)2-6, C6F5
R = H, Alkyl (Me, Et, nPr, Bn), Aryl (Ph, substituted Ph)
Scheme 7. Biomimetic reductive amination of fluorinated aldehy-
des and ketones.
37
38
36
N
R
F3C
CF3 R = H, OMe
Base,
Solvent
N
R
F3C
CF3
H
NH2
F3C
CF3
Scheme 8. Biomimetic transamination approach for preparation
3,5-bis(trifluoromethyl)benzylamine (38).
It is interesting to note that in some cases the isomerization
of 33 to 34 can take place even without a base, suggesting
much greater thermodynamic stability of the latter. Thus,
N-benzyl imine derived from trifluoro-acetophenone
33 (Rf = CF3, R = Ph) was quantitatively isomerized to
isomerized to Schiff base 34 simply by heating at 200 ºC for
N.V. Lyutenko et al.
7
40 4139
Rf OH
O
Rf N
H
O
Ph Rf N
Cl
Ph
i
ii
Rf N
Cl
Ph
Rf N Ph
Cl
Rf N Ph
Cl
Rf NH2
44 4543
42
Rf = CF3 (a); C2F5 (b); C3F9 (c)
Key: (i) BnNH2 (1 eq.), Ph3P (4 eq.)/CCl4 (4 eq.), TEA (1.5 eq.), CHCl3 reflux, 40 min.; (ii)
TEA (3 eq.)/H2O; (iii) MeOH/HCl (conc.), reflux, 24 h
iii
Scheme 9. Application of biomimetic transamination for preparation of amines from the corresponding carboxylic acids.
24 hrs. The target free amine 35 was isolated with excellent
(>95%) overall yield [47]. This biomimetic transamination
procedure can be easily scaled-up and represents the most
advanced preparation of amine 35 (Rf = CF3, R = Ph), the
fluorinated analog of highly biologically important
α-(phenyl)ethylamine.
This biomimetic transamination approach can be
extended to the derivatives in which trifluoromethyl group
is not directly attached to the azaallyllic system. For
example, 3,5-bis(trifluoromethyl)benzylamine 38 (Scheme
8), is a key pharmacophore found in numerous biologically
active compounds and drug candidates [48]. Therefore, this
compound was an exciting target for the biomimetic
transamination approach starting from commercially
available 3,5-bis(trifluoromethyl) benzaldehyde [49]. Initial
attempts to use benzylamine for the transamination of the
3,5-bis(trifluoromethyl) benzaldehyde resulted in a equilib-
rium shifted towards product 37 (85/15), albeit to a degree
of low synthetic application. Further optimization of the
reaction conditions (CH3CN as a solvent and DBU as a
base) and application of p-(methoxy)benzylamine allowed
for a noticeable shift in the equilibrium towards the desired
product 37 (95%), which was hydrolyzed to afford the
target amine 38 in 75% overall yield.
Of particular importance is the unique application of
biomimetic transamination for preparation of amines from
the corresponding carboxylic acids. This method involves in
situ formation of amides 40, their transformation to imidoyl
chlorides 41, followed by the first 1,3 proton transfer
affording imines 42. The next reaction step is a chlorotropic
shift to yield imines 43, which undergoes the second
1,3-proton transfer yielding 44. Imidoyl chlorides 44 can be
isolated and via two hydrolytic steps converted to the target
amines 45. Taking into account that the whole
transformation involves a sequence of seven reactions, the
excellent isolated yields (>90%) of amines 45 were quite
remarkable (Scheme 9) [50].
Due to very high reactivity, chemistry of fluorinated
dicarbonyl compounds is significantly complicated by the
issues of regioselectivity, enolate formation, and structural
liability (decomposition) towards nucleophilic reagents. For
example, reactions of 1,1,1,5,5,5-hexafluoro-2,4-pentane-
dione 46 (Scheme 10) with benzylamine gives rise to a
mixture of various inseparable products and therefore are of
no synthetic value. In sharp contrast to benzylamine, the
reaction of 2-picolylamine with dione 46 was found to be a
convenient approach of preparation of trifluoromethyl
containing myosmines 50. The whole process includes a
series of successive reactions such as formation of the direct
condensation product, imine 47, base-catalyzed 1,3 proton
transfer to form highly nucleophilic intermediate 48, its
cyclization to form five-membered 3,4-dihydro-2H-pyrrol-
3-ols 49, followed by the second base-catalyzed 1,3 proton
transfer to furnish the target myosmines 50. Compounds 50
can be isolated or directly dehydrated giving rise to 2-(2-
pyridyl)-3,5-bis-(trifluoromethyl)-1H-pyrrole 51 as a sole
reaction product [39]. It should be noted that equilibrium
48
5150
4746
49
F3C CF3
O O
N
NH2
F3C CF3
O N
N
F3C CF3
O N
HN
N
N
OH
CF3
F3C
N
N
OH
CF3
F3C
HN
N
CF3
F3C
Scheme 10. Biomimetic reductive amination approach of prepara-
tion of trifluoromethyl containing myosmines 50.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
8
54
52
56
5346
55
F3C CF3
O O
H2N
OH
Ph
N
O
F3C
CF3
Ph
DBU N
O
F3C
CF3
Ph
DBU
N
O
CF3
Ph
DBU
[1,2]-Wittig
N
Ph
F3C CF3
OH
-H2O
N
Ph
F3C CF3
57
F3C
Scheme 11. Biomimetic method for preparation of 2,4-bis(tri-fluoromethyl)-6-phenylpyridine.
6260
59
61
F3C COOEt
O
H2N
Ph
58
CH3COOH F3C COOEt
N Ph
TEA F3C COOEt
N Ph
H F3C COOH
NH2
Ph NH2
F3C COOEt
OH
HN
Ph
F3C
H
N
O
Ph + HCOOEt
63 64 65
F3C
OEt
O
H
Me Ph
F3C
N
OEt
OH
Ph
66 67
Scheme 12. Biomimetic synthesis of trifluoro-alanine.
between 47 and 48 significantly favors 47, however, the
irreversible cyclization of 48 to form products 48 followed
by biomimetic 1,3 proton shift, drives the reaction to
completion with the formation of myosmines 50 [51].
Another synthetically useful reaction of dione 46,
including the biomimetic isomerization step as a key
transformation, is presented in Scheme 11. Direct
condensation of dione 46 with glycinol 52 gave cyclic
product bis(trifluoromethyl)-2,3-dihydro-1,4-oxazepine 53.
Treatment of oxazepine 53 with a DBU initiated the
biomimetic 1,3 proton shift affording 1,4-oxazepine 54.
Intermediate 54 cannot be isolated, undergoing in situ yet
another DBU-catalyzed 1,3 proton transfer to yield one
more isomeric 1,4-oxazepine 55. Finally, DBU-catalyzed
[1, 2] Wittig rearrangement of 55 gave rise to 3,4-dihydro-
pyridin-3-ol 56. Dehydration of compound 56 resulted in
the formation of 2,4-bis(trifluoromethyl)-6-phenylpyridine
57 as a final reaction product [52]. One may agree, these
multi-step transformations clearly underscore very complex
chemistry of fluorinated dicarbonyl compounds.
Nevertheless, successful synthesis of interesting fluorine-
containing heterocyclic compounds under mild and metal-
free conditions bodes well for future application of
biomimetic approach in the chemistry of heterocyclic
biologically active compounds.
Fluorinated α-keto acids are highly electrophilic
compounds. For example, the reaction of keto ester 58
(Scheme 12) with benzylamine gives stable crystalline gem-
amino alcohol 63 which can be isolated and fully
characterized. However, attempts to dehydrate compound
63 to the corresponding imine under various conditions
usually result in the haloformic decomposition giving rise to
amide 64 and ester 65. To overcome the problem of
exceptionally high electrophilicity of fluorinated α-keto
acids, a special procedure was developed. As shown in
Scheme 12, keto ester 58 was reacted with a salts
α-(phenyl)ethylamine 59 to form the corresponding gem-
amino alcohol which gradually underwent acid-catalyzed
dehydration to furnish the target imine 60 in excellent
chemical yield (>95%) [53].
Biomimetic isomerization of Schiff base 60 to imine 61
can be quantitatively conducted at ambient temperature in
the presence of triethylamine. Acidic hydrolysis of 61
afforded the target trifluoroalanine 62 [54]. It should be
noted that application of enantiomerically pure
α-(phenyl)ethylamine allowed preparation of also
N.V. Lyutenko et al.
9
enantiomerically pure imine 60, triethylamine-catalyzed
isomerization of which resulted in completely racemic
amino acid 62. To explain this stereochemical outcome one
may propose that the proton transfer take place via six-
membered transition state 66 leading to achiral intermediate
enolate 67.
Due to the high biological value of fluorinated β-amino
acids [55] the biomimetic approach for reductive amination
of β-ketoacids is of great synthetic interest. As presented in
Scheme 13, derived from keto esters 68 and benzylamine,
imines 70 were cleanly isomerized to Schiff bases 71 on
heating at 75 ºC in the presence of triethylamine. It should
be mentioned that the equilibrium between enamine 69 and
imine 70 is nearly completely shifted towards the former.
Nevertheless, the very fast and irreversible biomimetic
isomerization of 70 affords Schiff bases 71 as the final
reaction products [56]. Acidic hydrolysis of imines 71
allows preparation of the target fluorinated β-amino acids
72 in high overall yield.
7069
7172
68
Rf
O
COOEt
Rf = CHF2, CF3, C2F5, C3F9, C4F9, H(CF2)2-6
H2N Ph Rf
N O
OEt
Rf
N O
OEt
H
Ph
Ph
TEA, 75 oC
Rf
N O
OEt
Ph
HRf
NH2
COOH
Scheme 13. Biomimetic approach to fluorinated β-amino acids.
75
7472
76
73
F3C
O
COOEt
H2N Ph F3C
N O
OEt F3C
N O
OEt
H
Ph Ph
TEA, 75 oC
F3C
N O
OEt
Ph
F3C
N O
OEt
Ph
(2R*,3S*) (2R*,3R*)
3N HCl
PhCH2COCl
77 78
F3C
NH O
OH F3C
NH O
OH
(2R*,3S*) (2R*,3R*)Penicillin
acylase
O
Ph
O
Ph
81 82
F3C
NH O
OH F3C
NH2 O
OH
(2S,3S) (2R,3R)
O
Ph
79 80
F3C
NH O
OH F3C
NH2 O
OH
(2R,3S) (2S,3R)
O
Ph
Scheme 14. Chemo-enzymatic approach for synthesis of all four possible stereoisomers of α-alkyl-β-fluoroalkyl-β-amino acids.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
10
This biomimetic approach for the reductive amination of
β-keto esters 68 is quite general and provides for the most
reliable and scalable preparation of biologically important
β-fluoroalkyl-β-amino acids 72. It should be noted that the
amino acids 72 are readily available in enantiomerically
pure form via specially developed enzymatic resolution of
the corresponding N-phenylacetyl derivatives using
penicillin acylase [57].
Combination of the biomimetic transamination and the
penicillin acylase catalyzed resolution was realized in a
chemo-enzymatic approach for synthesis of all four possible
stereoisomers of α-alkyl-β-fluoroalkyl-β-amino acids
(Scheme 14) [58]. Racemic starting keto ester 72 was
transformed into a mixture of enamine 73 and ketimine 74.
Biomimetic isomerization of 74 afforded diastereomers 75
and 76. Detailed investigation of this isomerization allowed
to find that the use of triethylamine as a base favored the
(2R*,3S*) diastereomer 75 (40% de), while the application
of DBU gave (2R*,3R*) diastereomer 76 as the major
product (39% de).
Diastereomerically pure 75 and 76, obtained by column
chromatography, were transformed to N-phenylacetyl
derivatives 77 and 78 and subjected to kinetic resolution
using penicillin acylase. The enzyme-catalyzed hydrolysis
of the enantiomers possessing (3R) stereogenic carbon was
extremely stereoselective with the rate of higher than 1 to
1000, thus allowing for a complete resolution with excellent
chemical yields of both enantiomers. Free (2S,3R)-80 and
(2R,3R)-82 can be easily separated from the corresponding
unhydrolyzed enantiomers (2R,3S)-79 and (2S,3S)-81,
which can be hydrolyzed under conventional acidic
conditions to produce the corresponding amino acids.
N
84
83
Rf R
NPh
Rf = CF3, C2F5, C3F7; R = Ph, CH2COOEt
(R)
Catalyst
84, 85
86
Rf R
NPh
N
OR
N
R = H, Me, Allyl, COPh, COMe
85
N
O
N
N
O
N N
84: up to 37% ee
85: up to 71% ee
Scheme 15. Asymmetric approaches for biomimetic reductive
amination.
Since the interest in fluorinated amines and amino acids
is associated with their biological applications in the design
of modern pharmaceuticals [59], the development of
asymmetric approaches for the biomimetic transamination
is particular interest. As shown in Scheme 15, series of
cinchonidine derived catalysts 84, and 85 were used to
perform catalytic asymmetric reductive amination of
ketimines 83. Due to relatively low basicity of chiral
catalysts 84 the isomerization reactions required high load
(50 mol%) of the catalyst and elevated temperatures [60].
The highest enantioselectivity obtained was only in the
range of 37% ee. A significant advance in this area has been
reported recently by J.C. Plaquevent et al. [61]. These
authors conduced a systematic study of all factors
influencing the enantioselective isomerization step and
found that C2 symmetric catalyst 85 allows the reaction to
proceed with up to 71% ee.
Another approach to asymmetric biomimetic reductive
amination of fluorinated ketones and keto acids can be
straightforward application of chiral α-(phenyl)ethylamine
in the place of benzylamine. It was found that triethylamine
is ineffective as a catalyst for the isomerization of ketimines
87. The reason for such a drastic difference in reactivity of
benzylamine and α-(phenyl)ethylamine is likely the
significantly reduced C-H acidity of the latter [62]. On the
other hand, application of a stronger base raised a due
concern of the products 88 racemization. It should be noted
that this type of asymmetric transformation involves the
enantioselective proton transfer from a less to a more C-H
acidic product. Thermodynamically, such enantioselective
process is forbidden. However, it can be successfully
conducted under kinetically controlled conditions, provided
that the isomerization step is substantially faster as
compared to the racemization of the target product.
Moreover, it was also expected that trifluoromethyl group
due to its steric bulk [44] and electrostatic features [45]
might have some protective role [63] slowing down the
undesired racemization process. Detailed investigation of
the isomerization of imine 87 to 88 revealed rather
unexpected results (Scheme 16). Thus, while racemization
was indeed a serious issue at high temperatures, virtually no
racemization was observed at ambient-to-60 ºC
temperature. The discovered DBU-catalyzed reaction
conditions were found to be of general synthetic use for
asymmetric biomimetic reductive amination of various
ketones and β-keto acids with good chemical yields and
high diastereoselectivity [64, 65].
87
Rf R
NPh
Rf = CF3, C2F5, C3F7; R = Me, Et, Bn, Ph, CH2COOEt
(R) 88
Rf R
NPh
DBU
50-60 oC
(S)
Yields: 74-94%
% ee: 87-97
Scheme 16. Stoichiometric asymmetric reductive amination.
It is interesting to note that the work on asymmetric
reductive amination of fluorinated ketones and keto acids
led to the discovery of Self-Disproportionation of
Enantiomers (SDE) [66] under the conditions of achiral
chromatography [67] and sublimation [68]. In particular,
fluorinated amines [69], α- [70], β-amino acids [71], and
alcohols [72] usually show very high magnitude of the SDE
allowing to use this phenomenon as enantiopurification
N.V. Lyutenko et al.
11
method. Nowadays, it is commonly accepted that the SDE
is the general phenomenon resulting in enantio-enriched
and enantio-depleted fractions anytime a chiral enantio-
merically enriched (not racemic or enantiomerically pure) is
subjected to physicochemical phase transition. General
recognition of the SDE prompted some academic journals
to require the SDE-tests as a part of submitted experimental
data [73].
Conclusions
In this review, we highlighted major synthetic and
methodological ideas which were developed in the area of
biomimetic reductive amination of fluorine-containing
carbonyl. Some of the methods have rather limited
application, while others offer quite practical synthetically
efficient solutions. Given the increasing importance of
fluorinated amino compounds in health-related research and
pharmaceutical industry, the biomimetic transamination
may be a method of choice providing the most convenient,
generalized, and greener (metal-free) approach to this class
of derivatives.
Notes
The authors declare no conflict of interest.
Author contributions. The manuscript was written
through contributions of all authors. All authors have
approved to the final version of the manuscript.
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Disproportionation of Enantiomers (SDE) to Ensure Accurate
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N.V. Lyutenko et al.
15
Біоміметичне трансамінування як загальний підхід до синтезу фторовмісних амінів
та амінокислот
А. Взорек1, Ц. Хань2, Н.В. Лютенко3*, M. Колей4, О.Є. Сорочинський3, Т. Оно5, В.A. Солошонок6,7
1 Інститут Хімії, Університет імені Яна Кохановського в Кельцях, Кельці, Польща
2 Нанкінський лісотехнічний університет, Нанкін, КНР
3 Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
4 CSIR-Центральний інститут досліджень скла і кераміки, Колката, Індія
5 Національний інститут передових промислових наук і технологій (AIST), Анагахора, Шімосідамі, Моріяма-ку, Нагоя, Японія
6 Університет Країни Басків, Сан-Себастьян, Іспанія
7 ІКЕРБАСК, Баскський фонд науки, Більбао, Іспанія
Резюме: Огляд присвячений відкриттю реакції азометин-азометинової ізомеризації фторованих N-бензилімінів та її подальшому розвитку в один
із найбільш зручних, масштабованих і доступних синтетичних методів отримання біологічно значущих фторованих амінів і амінокислот. Цей
метод, який зараз називають реакцією 1,3-протонного зсуву, широко використовується хіміками-органіками для синтезу різноманітних
фторованих аміносполук, які відіграють важливу роль у розробці сучасних фармацевтичних препаратів і агрохімікатів.
Ключові слова: біоміметичне відновне амінування; фторовані сполуки; аміни; α- і β-амінокислоти; раціональне конструювання ліків.
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| id | oai:ojs2.bioorganica.com.ua:article-72 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:15Z |
| publishDate | 2023 |
| 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/a0/a813dbcbb9d16d3b3452548f3d4643a0.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-722026-07-19T14:56:54Z Discovery of biomimetic transamination as a general synthetic method for preparation of fluorine-containing amines and amino acids Біоміметичне трансамінування як загальний підхід до синтезу фторовмісних амінів та амінокислот Wzorek, Alicja Han, Jianlin Lyutenko, Nataliya V. Koley, Manankar Sorochinsky, Alexander E. Ono, Taizo Soloshonok, Vadim A. biomimetic reductive amination fluorinated compounds amines α- and β-amino acids drug design біоміметичне відновне амінування фторовані сполуки аміни α- і β-амінокислоти раціональне конструювання ліків In this perspective review article, we describe the discovery of azomethine-azomethine isomerization of fluorinated N-benzyl-imines and its further development into one of the most convenient, scalable, and practical synthetic methods for preparation of biologically relevant fluorinated amines and amino acids. Currently referred to as 1,3-Proton Shift Reaction, this method is widely used by organic chemists for synthesis of variety fluorinated amino compounds playing important role in the design of modern pharmaceuticals and agrochemicals Огляд присвячений відкриттю реакції азометин-азометинової ізомеризації фторованих N-бензилімінів та її подальшому розвитку в один із найбільш зручних, масштабованих і доступних синтетичних методів отримання біологічно значущих фторованих амінів і амінокислот. Цей метод, який зараз називають реакцією 1,3-протонного зсуву, широко використовується хіміками-органіками для синтезу різноманітних фторованих аміносполук, які відіграють важливу роль у розробці сучасних фармацевтичних препаратів і агрохімікатів V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2023-12-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/72 10.15407/bioorganica2023.02.003 Ukrainica Bioorganica Acta; Vol. 18 No. 2 (2023): Ukrainica Bioorganica Acta; 3-15 Ukrainica Bioorganica Acta; Том 18 № 2 (2023): Ukrainica Bioorganica Acta; 3-15 1814-9766 1814-9758 10.15407/bioorganica2023.02 en https://bioorganica.com.ua/index.php/journal/article/view/72/71 Copyright (c) 2023 Alicja Wzorek, Jianlin Han, Nataliya V. Lyutenko, Manankar Koley, Alexander E. Sorochinsky, Taizo Ono, Vadim A. Soloshonok https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | біоміметичне відновне амінування фторовані сполуки аміни α- і β-амінокислоти раціональне конструювання ліків Wzorek, Alicja Han, Jianlin Lyutenko, Nataliya V. Koley, Manankar Sorochinsky, Alexander E. Ono, Taizo Soloshonok, Vadim A. Біоміметичне трансамінування як загальний підхід до синтезу фторовмісних амінів та амінокислот |
| title | Біоміметичне трансамінування як загальний підхід до синтезу фторовмісних амінів та амінокислот |
| title_alt | Discovery of biomimetic transamination as a general synthetic method for preparation of fluorine-containing amines and amino acids |
| title_full | Біоміметичне трансамінування як загальний підхід до синтезу фторовмісних амінів та амінокислот |
| title_fullStr | Біоміметичне трансамінування як загальний підхід до синтезу фторовмісних амінів та амінокислот |
| title_full_unstemmed | Біоміметичне трансамінування як загальний підхід до синтезу фторовмісних амінів та амінокислот |
| title_short | Біоміметичне трансамінування як загальний підхід до синтезу фторовмісних амінів та амінокислот |
| title_sort | біоміметичне трансамінування як загальний підхід до синтезу фторовмісних амінів та амінокислот |
| topic | біоміметичне відновне амінування фторовані сполуки аміни α- і β-амінокислоти раціональне конструювання ліків |
| topic_facet | biomimetic reductive amination fluorinated compounds amines α- and β-amino acids drug design біоміметичне відновне амінування фторовані сполуки аміни α- і β-амінокислоти раціональне конструювання ліків |
| url | https://bioorganica.com.ua/index.php/journal/article/view/72 |
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